Movement

Parkinsonism is a clinical syndrome defined by resting tremor, bradykinesia, rigidity, and gait disturbance[…].

The most common cause is levodopa-responsive Parkinson's disease[…].

Other DDX: drug-induced, vascular, and alpha-synucleinopathies[…] — including PSP, MSA, and DLB.

Risk factors: old age (>60), male sex, family history, rural geographic location, and gut dysbiosis[…].

Protective factors: ibuprofen use and coffee consumption[…].

The most common genetic risk factor is the GBA[…] mutation — suggestive of a more aggressive course with prominent cognitive decline[…].

PD is driven by degeneration of cells in the substantia nigra[…], leading to loss of dopamine transmission in the striatum[…] (caudate + putamen, part of the basal ganglia).

The Movement Disorders Society (MDS) PD clinical criteria require bradykinesia[…] (slowed movement with reduced amplitude) PLUS at least one of two cardinal motor features.

Cardinal feature 1: 4-6 Hz resting tremor[…], typically in just one limb.

Cardinal feature 2: rigidity[…] — increased resistance during passive movement, independent of direction or velocity.

Other common features NOT part of the MDS criteria: postural instability and gait freezing[…] (inability to step when initiating gait or turning).

Supportive criteria that strengthen the diagnosis: clear and dramatic response to dopaminergic[…] meds, levodopa-induced dyskinesias[…], olfactory neuron loss[…], and cardiac sympathetic denervation on MIBG[…] scintigraphy.

PD nonmotor symptoms include early constipation and hyposmia[…], cognitive impairment with neuropsychiatric features (mood changes), REM sleep behavior disorder[…], and autonomic dysregulation (HR, BP).

If diagnosis remains uncertain, options include: a levodopa trial[…] (dose >600 mg/day), skin biopsy[…] looking for alpha-synuclein, or DA-SPECT (DAT) imaging[…].

The gold standard for diagnosis is postmortem neuropathology[…] — showing atrophy of dopaminergic cells in the substantia nigra[…] without Lewy body or neurite accumulation in the rest of the brain.

On exam, look for masked facies[…] on facial expression. Sequential motor tests (proximal to distal): hands on lap with up/down movement, hands outstretched, finger tap, foot tap, full leg stomp, open/close hands.

Standing tests: hands on chest then stand; observe gait for shuffling, reduced arm swing, reduced stride length[…], freezing of gait, and en bloc turning[…].

PD has three motor phenotypes that predict course: Tremor-predominant[…]: resting tremor dominant; typically slower[…] disease progression.

Akinetic-rigid[…]: bradykinesia and rigidity predominate, less tremor; typically faster[…] progression.

Postural instability-gait disturbance (PIGD)[…]: parkinsonian gait with cognitive decline; less tremor/bradykinesia/rigidity.

DA-SPECT or DA-PET[…] imaging shows reduced[…] radiotracer uptake in the striatum — normal looks like a "comma" shape; abnormal looks like a period[…] shape.

Skin biopsy[…] detects phosphorylated α-synuclein[…] deposition — especially useful in PD presenting with early autonomic dysfunction.

MRI brain may show absence of the "swallow-tail[…]" sign on SWI, indicating degeneration of nigrosome-1 (usually a hyperintense structure within the hypointense SN).

Levodopa[…] is the most effective PD medication — a dopamine precursor that compensates for DA deficiency in the striatum.

It's combined with carbidopa[…] (brand: Sinemet) to reduce peripheral metabolism before CNS uptake, also decreasing GI side effects.

Efficacy is blunted over time as nigrostriatal neurons continue to die, producing the on-off[…] phenomenon.

Side effects: GI dysfunction, dyskinesias, hallucinations, and orthostatic hypotension[…].

DA Agonists (Ropinirole, Pramipexole, Rotigotine patch, subQ Apomorphine[…]) are synthetic dopamine analogs acting on postsynaptic receptors.

Distinctive side effects of DA agonists: GI dysfunction, orthostatic hypotension, excessive sleepiness with sleep attacks, BLE edema, and impulse control issues[…] (gambling, hypersexuality).

Amantadine[…] is an NMDA-receptor antagonist that stimulates DA receptors and blocks ACh receptors.

Amantadine's primary use is to suppress levodopa-induced dyskinesia[…] via glutamine blockade.

Amantadine's classic skin side effect is livedo reticularis[…]; other AEs include autonomic (constipation, dry mouth, BLE edema, urinary retention).

MAO-B inhibitors (Selegiline and Rasagiline[…]) inhibit MAO-B in glial cells, delaying DA breakdown in the synaptic cleft.

Key distinction: MAO-B inhibitors are different from MAO-A[…] inhibitors — which combined with SSRIs cause serotonin syndrome.

COMT inhibitors (Entacapone, Tolcapone, Opicapone[…]) [mnemonic: "Al Capone"] block peripheral levodopa metabolism, increasing CNS delivery.

Tolcapone[…] uniquely crosses the BBB to act both peripherally and centrally — but carries a black-box warning for hepatotoxicity[…].

Anticholinergics (Benztropine and Trihexyphenidyl[…]) are reserved for young patients without cognitive decline.

Adenosine A2A antagonists[…] (Istradefylline) reduce excessive inhibition of the indirect pathway of the basal ganglia, improving movement control. Side effect: dyskinesia.

Zonisamide[…] has DA-enhancing, glutamine-blocking, and Ca²⁺ channel effects.

For refractory motor symptoms, surgical/procedural options: Deep Brain Stimulation (DBS)[…]: electrodes implanted into the STN or GPi[…].

MRI-guided Focused Ultrasound[…]: creates lesions in deep brain structures without open surgery. Infusion therapies are also used in select cases (e.g., subcutaneous apomorphine, intraduodenal levodopa).

Dementia in PD: treat with AChE inhibitors[…], especially Rivastigmine[…].

Psychosis in PD: first discontinue offending agents in this order — anticholinergics → DA agonists → Amantadine → COMT inhibitors → reduce (don't stop) levodopa[…]. If psychosis is chronic, add an antipsychotic — but note these block DA and worsen motor symptoms.

The preferred choice is Pimavanserin[…], which has less DA affinity and fewer motor side effects. Apathy is another common neuropsychiatric symptom.

Neurogenic orthostatic hypotension is defined as SBP drop >20[…] mmHg or DBP drop >10[…] mmHg within 3 minutes of standing. Non-pharm: increase water and salt intake, use abdominal binder or compression stockings.

Pharm options: midodrine[…] (SE: supine HTN, piloerection); fludrocortisone[…] (avoid in CHF or ESRD); droxidopa[…] (SE: supine HTN from peripheral pressor effect).

Other autonomic symptoms: constipation, sialorrhea[…] (treat with glycopyrrolate, sublingual atropine, scopolamine patch, or Botox to salivary glands), urinary incontinence (treat with Mirabegron[…]), and sexual dysfunction (treat with PDE-5 inhibitors).

REM Sleep Behavior Disorder (RBD) is characterized by loss of muscle atonia during REM sleep[…], leading to movements from dream enactment.

RBD is an early biomarker linked to α-synucleinopathies[…].

Treatment: melatonin[…] (preferred) or clonazepam.

LBD includes two entities differentiated by the "1-year rule"[…]: Dementia with Lewy Bodies (DLB)[…]: cognitive symptoms appear <1 year after onset of PD motor symptoms; Parkinson Disease Dementia (PDD)[…]: cognitive symptoms appear >1 year after motor symptoms.

Pathophysiology: misfolded α-synuclein[…] protein creates Lewy bodies that deposit in largely dopaminergic areas.

Core DLB clinical features: Cognitive profile: early executive and visuospatial[…] dysfunction (planning, organizing, navigating). Tested with the top section of MoCA, trail-making, set-shifting, Wisconsin Card Sorting (executive); complex figure drawing or line-matching (visuospatial).

Cognitive fluctuations[…] through the day are a hallmark.

Visual hallucinations: often recurrent, complex, and well-formed[…] — including people or animals — occurring early in the disease course.

Other hallucination types: presence hallucinations, visual illusions, passage hallucinations, and Capgras syndrome[…] (a familiar person replaced by an identical-looking imposter).

DLB also features REM sleep Behavior Disorder (RBD)[…] and Parkinsonism.

MRI brain: generalized atrophy with preservation of the medial temporal lobes[…] (medial temporal atrophy would suggest AD instead). DA-PET or SPECT: reduced DA uptake in the basal ganglia.

FDG-PET: hypometabolism in the occipital[…] lobe with sparing of the posterior cingulate[…] — the classic "cingulate island sign[…]".

Reduced cardiac sympathetic innervation on MIBG[…] myocardial scintigraphy. Polysomnography: screens for RBD (REM sleep without atonia).

Quantitative EEG: PDR slowing below 8[…] Hz.

Skin biopsy shows α-synuclein[…]; CSF[…] α-synuclein seed amplification assay is also available.

DLB has three recognized prodromal presentations: Nonamnestic MCI[…].

Delirium[…] onset — treated inpatient with antipsychotics.

Psychiatric[…] onset — such as Capgras syndrome[…].

De-prescribe: anticholinergics, benzos, TCAs, and antipsychotics[…] — all worsen DLB cognition or motor sx.

AChE inhibitors[…] (Donepezil, Rivastigmine) especially help with neuropsychiatric symptoms like psychosis. Side effects: GI upset, bradycardia.

Antipsychotics (Quetiapine/Seroquel[…]) help with psychosis but cause QTc prolongation.

Melatonin or clonazepam[…] for RBD (good replacement for benzos).

Levodopa or Zonisamide[…] for parkinsonism.

Tremor is alternating contraction of antagonist muscle group pairs[…].

Metabolic triggers to rule out: thyroid dysfunction, hyperparathyroidism, hypoglycemia[…].

Iatrogenic triggers (drugs) to rule out: caffeine, mood stabilizers (lithium[…]), ADHD meds (amphetamines), epilepsy meds (VPA, lamotrigine[…]), asthma LABAs, amiodarone, Reglan, alcohol, tacrolimus. Also rule out enhanced physiologic tremor (worse in stressful situations).

Tremor mimics to recognize: myoclonus[…] (muscle jerks; polyminimyoclonus[…] = bilateral irregular jerky twitching of outstretched hands in MSA/CBD/ALS), dyskinesia[…] (irregular multi-directional movement, e.g., tardive dyskinesia with orolingual movements), and ataxia[…] (limb/truncal with slow 1-2 Hz cerebellar tremor).

Head tremor: test by looking straight then turning head to side, holding briefly ("yes-yes" or "no-no" movements). Facial tremor: especially seen with enhanced physiologic or essential tremor. Jaw/lower lip tremor: jaw open[…] in essential tremor (ET); jaw closed[…] in PD. Voice tremor: noted when saying "eeeee" or "aaaahhh" for several seconds. Also assess arm/hand and leg/foot tremor.

First-line agents for essential tremor:. Propranolol[…] 40-80 mg BID or TID. Side effects: constipation, exercise intolerance, lightheadedness.

Primidone[…] 12.5-250 mg/day.

Side effects: induces CYP450 (interacts with warfarin/DOACs), ataxia, and sedation[…].

For head tremor and voice tremor specifically: Botox[…] injections to the laryngeal muscles.

For refractory tremor, surgical options: DBS[…] (unilateral or bilateral) to the thalami[…].

Unilateral Focused Ultrasound Thalamotomy[…] with MR thermometry — ablates the VL (ventral intermediate)[…] nucleus of the thalamus.

The Fahn-Tolosa-Marin scale grades tremor severity from 0-4: 0: no tremor; 1-2: mild, present some of the time; 3: marked amplitude (2-4 cm[…]), interferes with most activities; 4: severe (>4 cm[…]), handwriting/eating/drinking impossible.

Tremor frequency: <4 Hz[…] (low) → 4-8 Hz → 8-12 Hz → >12 Hz.

MSA has typical onset in the 50s[…] with fast progression — mortality ~6-10 years from onset.

Two subtypes: P-MSA[…]: levodopa-responsive parkinsonian variant; C-MSA[…]: cerebellar variant.

MSA pathology: misfolded α-synuclein[…] aggregates in oligodendrocytes[…] — forming glial cytoplasmic inclusions.

This causes atrophy of: The nigrostriatal[…] system in P-MSA; The olivopontocerebellar[…] system in C-MSA.

Affected structures include the putamen, pons, inferior olives (medulla), and autonomic[…] brainstem and spinal cord nuclei.

MSA motor symptoms span 4 categories: Extrapyramidal: Parkinsonism with emphasis on postural and action tremor[…] (vs resting in PD), polyminimyoclonus[…], masked facies, dysarthria, dysphagia, sialorrhea, gait/postural instability with recurrent falls.

Dystonias like anterocollis[…]. Cerebellar ataxia symptoms: gait or limb ataxia, scanning speech, ocular ataxia.

Pyramidal signs: hyperreflexia and spasticity[…].

Orthostatic hypotension in MSA: SBP drop >20[…] mmHg or DBP drop >10[…] mmHg within 3 minutes from supine to standing.

Other autonomic features: urinary dysfunction[…] (retention, incontinence), GU dysfunction (sexual dysfunction, piloerection), anhidrosis[…], and constipation.

REM Sleep Behavior Disorder[…] is also common in MSA.

Respiratory stridor[…] is a red flag — concerning for sudden respiratory failure/death while asleep due to laryngeal muscle dysfunction.

MRI Brain: the "hot cross bun sign[…]" — hyperintensity in the pons from pontocerebellar fiber degeneration with preserved CST.

In P-MSA: posterior putamen[…] atrophy with a "hyperintense rim" sign.

In C-MSA: pontine atrophy with middle cerebellar peduncle[…] atrophy. DA-PET/SPECT: loss of DA transporter uptake (nonspecific — also in PD, DLB, PSP). FDG-PET: hypometabolism in the putamen, brainstem, and cerebellum.

Key distinction from PD: MSA has normal MIBG[…] scintigraphy (PD has reduced) — MSA's lesions are preganglionic.

Per the International Parkinson & Movement Disorder Society 2022 Criteria for MSA, the patient needs: Progressive onset at >30[…] years old.

Autonomic dysfunction with at least one of: orthostatic hypotension, or urinary dysfunction with PVR >100 mL[…] or urge incontinence.

Plus Parkinsonism (rigidity, tremor, postural instability with poor levodopa response) OR cerebellar symptoms[…] (ataxia, ocular ataxia). Supportive criteria: at least two imaging findings, skin biopsy for α-synuclein, or seed amplification assay.

Definitive diagnosis requires neuropathology showing α-synuclein-positive glial cytoplasmic inclusions[…] with neurodegeneration of nigrostriatal or olivopontocerebellar pathways.

Parkinsonism in MSA: studies have shown nothing[…] to be effective — unlike PD, MSA is poorly levodopa-responsive. Dysarthria: speech therapy. Dysphagia: PEG tube placement.

Spasticity: muscle relaxants (Flexeril, baclofen[…]) or focal Botox injections.

Dystonia: Botox[…] for focal dystonia; for generalized: anticholinergics, DA agonist/levodopa reduction, muscle relaxants. Cerebellar symptoms: no proven effective treatment.

For neurogenic orthostatic hypotension in MSA: First steps: discontinue antihypertensives and anti-DAminergic drugs; increase water and salt[…] intake.

Medications: Midodrine[…]: α1 agonist; watch for supine HTN[…]; Droxidopa[…]: norepinephrine precursor; Atomoxetine[…]: norepinephrine reuptake inhibitor; Pyridostigmine (Mestinon)[…]: AChE inhibitor; Florinef (fludrocortisone)[…]: but long-term use risks CHF and renal fibrosis.

Overflow incontinence: α1 blockers[…] (tamsulosin, prazosin) to relax urethra — but can worsen orthostatic hypotension.

Urgency incontinence: β3 agonists[…] like Mirabegron, or antimuscarinics like solifenacin (minimal CNS penetration).

Stress incontinence: surgery/slings; chronic dysfunction often requires catheter (foley or suprapubic)[…].

Constipation: avoid opioids and anticholinergics; use promotility agents (linaclotide, prucalopride[…]) and laxatives.

Sexual dysfunction: PDE-5 inhibitors[…] (sildenafil). RBD: melatonin + clonazepam.

Stridor: CPAP[…] progressing to permanent tracheostomy.

PSP and CBS are clinically seen as atypical Parkinson-spectrum[…] disorders, but pathophysiologically fit within the FTD[…] spectrum (along with ALS-FTD, bvFTD, svPPA).

PSP is also known as Richardson Syndrome[…].

Pathophysiology: pathologic accumulation of mostly 4-repeat tau[…] isoforms — making PSP and CBS types of tauopathies[…].

Early signs (<3 years from onset):. Backward[…] falls (vs forward falls in PD).

Ataxic gait with postural instability — way more clumsy than PD — with heel pivot turns and retropulsion[…] (unlike en bloc turns in PD).

The "rocket sign[…]" — patient propels out of their chair when standing without assistance, often falling — due to impaired visual-vestibular system and impulsivity.

Ocular signs (hallmark):. Vertical[…] gaze palsy with restricted upgaze[…] — eventually progresses to also affect horizontal gaze (fixed gaze and stare).

Very slow downward saccades[…], including the "round-house sign[…]" — eyes arc downward through horizontal centers to move along midline.

"Square wave jerks[…]" — brief bilateral conjugate horizontal micro-saccades.

The "sunglasses sign[…]" — patient wears sunglasses inside due to photosensitivity. Facial signs:

Early (<3 years) dysarthria[…] often described as "growling" or hypernasal, plus early swallow difficulty.

Astonished look[…] with frontalis activation but otherwise masked facies.

Cognitive symptoms in PSP: Pseudobulbar affect[…] — most common in PSP among parkinsonian syndromes. Depressive mood (apathy, withdrawal).

FTD-spectrum cognitive impairment[…] with perseveration — the classic "applause sign[…]" where patients keep clapping more than the 3 times they were instructed.

Vascular PSP: characterized by lower extremity[…]-predominant Parkinsonism.

Normal Pressure Hydrocephalus (NPH): gait freezing ("magnetic" gait[…]), falls, urinary symptoms, cognitive symptoms, and vertical gaze palsy (usually upward only — unlike PSP which is both up and down[…]).

Mokri Syndrome[…] (associated with aortic surgery): triad of dysarthria, supranuclear gaze palsy (including downward), and gait imbalance.

IgLON5 encephalitis[…]: bulbar symptoms, gait ataxia, chorea, upward gaze palsy, cognitive impairment.

LGI1 encephalitis[…]: limbic encephalitis, faciobrachial dystonic seizures[…], hyponatremia.

DPPX encephalitis[…]: hyperexcitability, dysautonomia.

MRI Brain[…] is the most helpful tool, showing midbrain atrophy[…]:

"Hummingbird sign[…]" on sagittal; "Mickey Mouse[…]" sign (reduced AP diameter) or "Morning Glory[…]" sign (reduced lateral margins) on axial; Superior cerebellar peduncle[…] atrophy on axial.

CBD presents with early, marked asymmetric[…] limb dysfunction — featuring bradykinesia or akinesia + rigidity, dystonia, or spasticity.

This leads to early difficulty with sequenced movements (cutting with scissors, using a screwdriver) — called ideomotor apraxia[…].

Myoclonus[…] that's often stimulus-sensitive (similar to CJD) but with gradual onset (>1 year) unlike CJD.

Some patients develop the alien limb[…] phenomenon — feeling the limb is foreign.

Similar to PSP: early difficulty with speech, swallowing, or vertical gaze palsy[…].

Progressive parkinsonism with later-onset gait instability and frontal-predominant cortical dementia[…] with behavioral changes — often unresponsive to levodopa[…].

MRI Brain or FDG-PET:. Asymmetric[…] superior parietal lobule[…] atrophy or hypometabolism, especially involving the perirolandic gyri[…] (precentral + postcentral gyrus).

Often posterolateral or medial frontal[…] atrophy. May see atrophy of subcortical structures (bilateral basal ganglia or striatum).

Parkinsonism: Sinemet trial[…] may have partial response early; DA agonists don't help and have AEs; avoid anticholinergics due to cognitive AEs.

Ocular symptoms: sunglasses[…] for dry eyes, photophobia, and diplopia.

Cognitive symptoms: AChE inhibitors[…].

Caution: benzodiazepines[…] should be used very cautiously — some studies show more rapid disease progression.

Dystonia is defined as sustained or intermittent muscle contractions[…] causing repetitive twisting or posturing movements — often initiated or worsened by voluntary action.

Most commonly we see adult-onset focal[…] dystonia.

An autosomal dominant, early-onset form of generalized dystonia presenting in adolescents is associated with the TOR1A[…] gene.

Adult-onset focal dystonia presentations (head to toe): Blepharospasm[…]: eyelids; Oromandibular dystonia[…]: mouth/jaw (different from hemifacial spasm); Cervical dystonia[…]: neck; Laryngeal dystonia[…]: voice; Limb dystonia.

Focal dystonia can sometimes secondarily generalize[…] (like a seizure). Sensation is typically normal in dystonia.

Task-specific hand/limb dystonia subtypes: writer's cramp[…] (only when writing), musician's dystonia[…] (playing piano), or sports dystonia (golfing, baseball).

Nonmotor symptoms — particularly psychiatric[…] symptoms — are increasingly recognized.

Childhood-onset dystonia commonly starts focal[…] then secondarily generalizes (unlike adult focal forms).

A common type is associated with the TOR1A[…] gene — caused by a 3-base pair (GAG) deletion[…] — often starting in a limb then spreading to other limbs and torso.

Another common subtype is levodopa-responsive dystonia[…], which can show signs of mild Parkinsonism.

Dystonia symptoms commonly worsen with infections[…] (systemic inflammation triggers).

Drugs/toxins: DA stimulants or blockers[…], antidepressants (SSRIs, SNRIs, TCAs), lithium[…], stimulants (legal or cocaine).

Acquired causes: autoimmune/paraneoplastic encephalitis[…]. Neurodegenerative conditions producing dystonia: PD (+bradykinesia/resting tremor); MSA (+autonomic dysfunction); PSP (+vertical gaze palsy/falls); CBD (+full limb rigidity/alien limb); DLB (+dementia/hallucinations).

Metabolic causes: Wilson disease (Cu accumulation)[…]; in kids — galactosemia, GLUT-1 deficiency, Niemann-Pick, abetalipoproteinemia.

Oral (mostly for generalized dystonia):. Anticholinergics[…] (trihexyphenidyl[…]), antidopaminergics (levodopa)[…], muscle relaxants (baclofen[…], off-label benzos). Injectables (especially for focal dystonia):

Botox injections[…] — especially effective for cervical dystonia and blepharospasm[…]. Surgeries:

DBS[…] to the GPi or STN[…] — especially effective in kids with TOR1A[…]-associated dystonia. Focused ultrasound with pallidotomy/thalamotomy.

Chorea derives from "choreia" meaning dance[…] — describing random, unpredictable movements with varying frequency/amplitude.

Mild forms may be mistaken for restlessness or fidgetiness[…].

The most severe form is ballism[…] — high-amplitude movements involving proximal joints (entire limb).

Distinguishing chorea from other hyperkinetic movements: Dystonia: slower and more sustained[…]; often patterned; may have a sensory trick[…] (e.g., touching the area to relieve) or a null point[…].

Myoclonus: faster and more jerky[…]; positive (gain of muscle tone) vs negative (loss of tone) variants; no flowing quality.

Tics: have a premonitory urge[…] and release phenomenon.

Athetosis: continuous flowing movement[…] — appears as "piano-playing fingers" in distal extremities.

Most common cause of chorea overall: Huntington disease[…]. Forehead chorea: often caused by anti-DA medications.

Orobuccolingual[…] chorea (mouth and tongue): most common cause is tardive dyskinesia[…] from anti-DA meds; also seen with anti-NMDA encephalitis.

Hemibody chorea: associated with lesions in the contralateral subthalamic nucleus (STN)[…], BG, thalamus, corona radiata, or temporoparietal region.

Other common causes: Sydenham's chorea[…] after GAS infection (check ASO, anti-DNase Ab; treat with PCN), polycythemia vera[…], and toxic-metabolic etiologies.

Acute-subacute timing: suspect paraneoplastic/autoimmune encephalitis (IgLON5)[…], DA-altering meds, SLE.

Chronic timing: suspect genetic etiologies[…].

Huntington disease is an autosomal dominant disorder caused by an excessive CAG trinucleotide repeat expansion[…] in the HTT[…] gene on chromosome 4. Normal: ~20 repeats.

HD: >40[…] repeats. The mutated huntingtin protein causes progressive degeneration of medium spiny neurons in the striatum.

Genetic anticipation[…] — higher repeat counts → earlier onset, more severe disease.

Juvenile-onset HD (Westphal variant[…]) can have >80 repeats.

Initial symptoms in HD: Cognitive decline[…] — subcortical, frontal dementia.

Psychiatric symptoms[…] — any type, including suicidal ideation (a common cause of death along with PNA/infection). Later symptoms:

Chorea[…] — especially involving the forehead (unlike tardive dyskinesia) — can affect speech, swallowing, breathing muscles.

Slowed and delayed saccades[…] with saccadic intrusions of smooth pursuit; eventually requires head-turning to initiate eye movement.

HD Imaging: CTH or MRI shows progressive atrophy globally, most notable in the caudate nucleus[…], with expansion of the anterior horns of the lateral ventricles — the "boxcar ventricles[…]" appearance.

Measured by reduced frontal horn:intercaudate (FH/CC) ratio[…] (caudate shrinking) or increased intercaudate:inner table (CC/IT) ratio[…].

Phenocopies (workup if genetic testing for HD is negative): C9orf72[…] disorders → FTD-ALS; SCA17[…] → Spinocerebellar ataxia; ATN1[…] mutation → Dentatorubral Pallidoluysian Atrophy; Primary Familial Brain Calcification (Fahr Disease[…]); Chorea-Acanthocytosis[…]; Niemann-Pick Type C[…] (NPC mutation); Wilson's Disease[…] (ATP7B gene; low ceruloplasmin, high urine Cu, Kayser-Fleischer rings).

Remove the underlying insult first (antipsychotic in TD, PLEX in AIE, PCN in Sydenham's, etc.). VMAT2 inhibitors[…] interrupt DA placement into presynaptic vesicles, reducing nigrostriatal pathway activation → reducing chorea:

Tetrabenazine[…] (TETRA-HD Trial) — black-box warning for SI[…]; Deutetrabenazine[…] (ARM-TD/AIM-TD/First-HD; brand: Austedo) — SI warning; Valbenazine[…] (KINECT 3) — prodrug of tetrabenazine, less SI but QTc prolongation[…].

All cause sedation, headache, and akathisia[…].

Postsynaptic D2 receptor inhibitors[…] (neuroleptics/antipsychotics) suppress chorea by preventing nigrostriatal pathway activation:

Olanzapine[…]; Risperidone[…]; Aripiprazole[…]. Newest treatments (miRNA therapy) — Sept 2025 preliminary UK trial showed >75% slowing of clinical progression:

Mechanism: modified viral vector[…] infused into caudate + putamen delivers DNA encoding microRNA[…] → intercepts huntingtin mRNA → lowers huntingtin protein levels.

The cerebellum has two hemispheres connected by the vermis[…] and three lobes:

Anterior lobe[…] = the "spinocerebellum"; Posterior lobe[…] = most of the lateral hemispheres; Flocculonodular lobe[…] = the "vestibulocerebellum" (input from vestibular CN nuclei and midbrain pretectal area).

The cortex (gray matter layer) contains, from outside in: molecular layer → Purkinje layer → granule layer[…].

Deep cerebellar nuclei (in white matter): Dentate[…] nuclei: input from lateral hemispheres; Fastigial[…] nuclei: input from vermis; Globose + emboliform[…] = interposed nuclei: input from lateral intermediate zone.

Afferents (input):. Inferior olives[…] (medulla) → climbing fibers → through inferior cerebellar peduncle[…].

Corticopontine pathways → pons → mossy fibers → through middle cerebellar peduncle[…]. Efferents (output):

Deep cerebellar nuclei → superior cerebellar peduncle[…] → VL thalamic nucleus + red nucleus[…]. Three peduncles:

Superior[…]: dentatorubrothalamic tract (dentate → contralateral → red nucleus → contralateral VL thalamus); Middle[…]: afferents from pontocerebellar tract; Inferior[…]: afferents from spinal cord and vestibular system (spinocerebellar, cuneocerebellar, trigeminocerebellar, olivocerebellar, vestibulocerebellar).

Sensory ataxia results from damage to peripheral nerves[…] (e.g., neuropathy) → dysfunction of proprioceptive information ascending via the spinocerebellar[…] tracts laterally or the DCML[…] pathway posteriorly.

Lesions in the DRG[…] can also produce sensory ataxia.

Classic exam findings: high-steppage gait[…] and positive Romberg sign[…].

Gait dysfunction: wide-based, unsteady gait[…] with tendency to veer to a side (like ETOH intoxication) — making turning difficult.

Posture dysfunction: imbalance with truncal swaying; inability to perform tandem, heel-to-toe, or single-leg standing[…]. In sensory ataxia, this worsens with eyes closed.

Speech dysfunction: scanning speech[…] — slow rate, abnormal consonant production, distortion of vowels, with each syllable pronounced slowly with irregular pausing.

Dysmetria[…] = inability to modulate distance of movements: Finger-Nose-Finger (FNF)[…] test; Finger Chase test; Heel-to-Shin test; Failure = overshooting the target.

Dysdiadochokinesia[…] = inability to coordinate fast alternating movements: Rapid Alternating Movements (RAM)[…] test; Failure = unable to coordinate back/forth hand flap on lap.

Ocular dysfunction in cerebellar disease:. Nystagmus[…] — eyes darting back/forth.

Downbeat nystagmus is classic in SCA type 6[…]. Saccadic dysmetria: hypometria (undershooting) or hypermetria (overshooting). Square wave jerks (like PSP).

Impaired smooth pursuit[…] — common in Friedreich ataxia.

Ocular flutter and opsoclonus — common in paraneoplastic[…] disorders. Tremors:

Intention tremor[…] — worsens as patient nears target (best seen on FNF and H2S testing).

Rubral (Holmes) tremor[…] — low-frequency (~4.5 Hz) tremor with combined resting/postural/action components; caused by midbrain lesions in red nucleus pathways.

Cognitive: Cerebellar Cognitive Affective Syndrome (Schmahmann Syndrome)[…].

Vascular: stroke or hemorrhage. EtOH toxicity[…]: chronic use shows atrophy of the anterior vermis[…].

Paraneoplastic[…]: anti-gliadin, anti-GAD, anti-Yo, anti-Hu, anti-Ri Abs; rarely anti-TPO/TRG.

Iatrogenic: phenytoin[…].

Metabolic: Wilson disease (striatum/thalamic hyperintensities on MRI), B12/folate/B1/Vit E deficiency[…], Wernicke's (mammillary body hyperintensities), heavy metal poisoning. Neoplastic: cerebellar tumors or tumors along afferent/efferent pathways.

Autoimmune: MS, NMO, MOGAD, Celiac[…] disease. Infectious: neurosyphilis, infectious abscess.

Friedreich Ataxia[…]: caused by GAA trinucleotide repeats[…] on chromosome 9 → misfolded frataxin[…] protein. May show thinning of the cervical spinal cord on MRI. Apart from ataxia: DM2, cardiomyopathy (cause of premature death), scoliosis.

Fragile X-Associated Tremor & Ataxia Syndrome (FXTAS)[…]: caused by CGG repeats in FMR1[…]; shows the "middle cerebellar peduncle sign[…]" in the pons.

Spinocerebellar Ataxias (SCAs)[…]: many linked to CAG trinucleotide expansion[…] with genetic anticipation (like HD). Most common: type 3 > type 2 > type 6. Type 27 is increasing in prevalence in adult sporadic-onset.

Episodic Ataxias: linked to channelopathies[…] (K⁺ and Ca²⁺).

Ataxia-Telangiectasia[…]: ATM gene mutations; presents with conjunctival telangiectasia, oculomotor apraxia, immunodeficiency, and movement disorders.

Increased risk of leukemia and lymphoma[…].

Neurodegenerative ataxia causes: MSA-C[…]: +parkinsonism +RBD +autonomic; "Hot Cross Bun[…]" sign in pons.

CJD[…]: rapid onset, startle myoclonus.

CANVAS[…] (Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome): atrophy of cerebellar vermis and lateral hemispheres; caused by AAGGG repeat expansion in the RFC1 gene[…]; often heralded by chronic dry cough[…].

Mitochondrial diseases[…]: Kearns-Sayre, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes).

Gerstmann-Sträussler-Scheinker Syndrome[…]: PRNP gene mutations on chromosome 20.

Pantothenate kinase-associated neurodegeneration (PKAN): GPi hyperintensities → "pseudo eye of the tiger[…]" sign.

The only FDA-approved pharmacologic treatment for an inherited ataxia is for Friedreich Ataxia: Omaveloxolone[…], an Nrf2[…] activator.

Classifications:. Motor tics[…] = movements (sniffing, throat clearing, grunting, torticollis, jaw opening, blinking, blepharospasm).

Often start in the craniofacial[…] region → spread to trunk → then limbs.

Vocal/phonic tics[…] = sounds (echolalia, palilalia, coprolalia). Usually develop after motor tics are established. Characteristics:. Tics are quick, recurrent, nonrhythmic; can be semivoluntary or involuntary.

Premonitory urge[…] relieved after the tic — somatic (muscle tension/itch), psychosomatic (inner restlessness), or "just right urge[…]". Pathophysiology:

Dysregulation of cortico-striato-thalamo-cortical circuits[…] → disinhibition of DA, serotonin, and GABA pathways — located in SMA, associative PFC (also involved in ADHD[…]), and limbic orbitofrontal PFC (also involved in OCD[…]).

Tourette Syndrome diagnostic threshold: at least 1 phonic tic + 2+ motor tics[…] for >1 year, starting <18 years of age.

Primary tic disorders:. Tourette Syndrome[…]: multiple motor tics + at least one phonic tic >1 year duration, <18 yo onset.

Chronic Motor Tic Disorder[…]: only motor tics, no phonic tics.

Chronic Vocal Tic Disorder[…]: only vocal tics, no motor tics.

All exacerbated by anxiety or sleep deprivation[…]. Secondary tic disorders:

Developmental: autism[…]. Drugs: neuroleptics, lamotrigine, carbamazepine, cocaine/stimulants, caffeine.

Genetic: Wilson disease[…], Huntington disease, CJD, neuroacanthocytosis. Toxins: O₂ deficiency (HIE, stroke), CO poisoning. CNS infections: neurolyme, neurosyphilis, viral encephalitis.

Functional Tic-Like Behaviors (FTLB)[…]: often distractible (unlike true tics).

Non-distressing tics: no treatment needed[…]. Tourette's medications (by age):

Haldol[…] if very young (3+); Aripiprazole[…] (6+); Pimozide[…] (12+ teen-adult).

For refractory cases (selectively chosen, with ethics consult): DBS[…] to anteromedial GPi + centromedian-perifascicular-thalamic complex. With comorbidities:

OCD: CBT first-line[…] → SSRIs → antipsychotics.

ADHD: stimulants (methylphenidate, atomoxetine[…]) or α2 agonists[…] (guanfacine > clonidine; less sedation). SE: bradycardia, hypotension, rebound HTN if discontinued. Behavioral interventions:

Exposure and Prevention Therapy[…]: teaches tic-resisting behaviors.

Habit Reversal Therapy[…]: identify triggers and substitute a voluntary competing response.

CBIT[…] (Comprehensive Behavioral Intervention for Tics): combination of the above.

Primary paroxysmal movement disorders (mostly genetic): Paroxysmal Kinesigenic Dyskinesia[…] (most common): PRRT2[…] gene mutation. Chorea-dystonia attacks triggered by sudden voluntary movements (standing, walking, running).

Paroxysmal Nonkinesigenic Dyskinesia[…]: PNKD[…] gene. Chorea-dystonia attacks triggered by strong emotion, fatigue, or caffeine.

Paroxysmal Exercise-Induced Dyskinesia[…]: SCL2A1[…] glucose transporter gene. Chorea-dystonia provoked by exercise for a few minutes.

Paroxysmal Nocturnal Dyskinesia[…]: ADCY5[…] gene. Occurs during sleep (stages N2 and REM); EEG shows no electrographic correlate.

Paroxysmal Alternating Hemiplegia of Childhood[…]: often provoked by stress.

Episodic Ataxia: KCNA1[…] (K⁺ channelopathy), CACN or UBR4 (Ca²⁺ channelopathy), SLC1A3 (glutamate channelopathy).

Secondary paroxysmal movement disorders:. LGI1 encephalitis[…]: faciobrachial dystonic seizures[…] (often <3 seconds) involving the ipsilateral face and arm + hyponatremia[…] + episodic bradycardia.

NMDA encephalitis[…]: paroxysmal dystonic posturing[…] preceding encephalitis.

CASPR2 or Hashimoto encephalitis[…]: paroxysmal kinesigenic dyskinesias + seizures + cognitive impairment.

Vascular: contralateral ICA stenosis or Moya-Moya disease[…] with episodic limb shaking.

Metabolic: aberrancies in glucose, Ca²⁺, or TSH[…].

Diagnosis: the most important step is obtaining genetic testing[…].

Treatment for most paroxysmal disorders: antiseizure medications[…] targeting Na⁺ and glutamate channels:

Phenytoin, Carbamazepine, Lamotrigine[…].

Note: ASMs are typically NOT effective for Paroxysmal Nonkinesigenic Dyskinesia[…].

Episodic ataxia: acetazolamide[…].

Rare refractory Paroxysmal Kinesigenic Dyskinesias: thalamotomy[…] of the ventro-oral thalamic nucleus. Also: trigger avoidance and treat underlying etiology.

In a PD patient with violent sleep behaviors and vivid dream recall, polysomnography most likely shows increased phasic EMG activity during REM periods[…] — characteristic of REM Sleep Behavior Disorder (RBD)[…].

A patient on breast cancer chemotherapy who develops oscillopsia, tremor, and gait ataxia with normal MRI most likely has neurotoxicity from a taxane[…] chemotherapeutic (paclitaxel, docetaxel), which acts by stabilizing microtubule polymers.

These drugs can cause acute cerebellar[…] dysfunction even without MRI findings.

The subthalamic nucleus (STN)[…] is involved ONLY in the indirect motor basal ganglia pathway.

The globus pallidus interna, putamen, substantia nigra pars reticulata, and VL nucleus[…] are involved in BOTH the direct and indirect pathways.

Quick mechanisms of PD drugs: Trihexyphenidyl[…] (anticholinergic) treats parkinsonian tremor by blocking ACh (the "brake") in movement pathways.

Levodopa/carbidopa[…] increases dopamine.

Rasagiline[…] boosts dopamine by inhibiting MAO-B.

Amantadine[…] acts on the glutamate system.

FXTAS presents with late-onset ataxia, tremor, and cognitive decline[…], caused by a CGG repeat expansion[…] in the FMR1 gene.

MRI may show white matter changes in the middle cerebellar peduncle and splenium of the corpus callosum[…].

Progressive cerebellar syndrome in a woman with ovarian cancer is most often due to anti-Yo[…] antibody (PCA-1) — the classic marker for paraneoplastic cerebellar degeneration associated with gynecologic[…] malignancies.

Unidirectional head tremor[…], especially with abnormal cervical posturing or relief from a sensory trick[…], is most consistent with dystonic tremor[…].

Essential tremor is typically symmetric, postural/kinetic[…], and does NOT improve with sensory tricks.

Sudden hemiparesis with a positive Hoover sign[…], normal MRI, and no organic disease is classic for functional neurologic disorder (conversion disorder)[…]. Diagnosis relies on internal inconsistency and clinical features.

The best treatment to reduce chorea in Huntington disease is the VMAT2[…] inhibitor deutetrabenazine[…], also called Austedo.

Quick antibody-syndrome associations: Stiff-person syndrome: anti-GAD65[…] Ab.

Hereditary spastic paraplegia: SPG4[…] gene.

CASPR2[…] antibody: associated with Morvan syndrome and neuromyotonia[…].

SCN[…] mutations: channelopathies.

Climbing fiber cell bodies arise from the inferior olivary nucleus[…].

Dextromethorphan[…] overdose can cause dyskinesia.

Diphenhydramine[…] treats rather than induces dystonia (especially acute dystonic reactions).

For RBD in Parkinson disease with intolerance to clonazepam, melatonin[…] is preferred.

Tourette syndrome features both motor tics and vocal tics[…], usually suppressible[…] and recurrent.

Loss of olfactory[…] function (hyposmia/anosmia) is a prodromal marker for Parkinson disease.

Miller Fisher syndrome triad: ophthalmoplegia, ataxia, and areflexia[…].

Associated with anti-GQ1b[…] antibodies.

The cell type most affected in anti-Yo antibody cerebellar degeneration is the Purkinje cell[…] — due to selective antibody binding to cytoplasmic antigens CDR2 and CDR2L.

Amiodarone[…] commonly induces bilateral, postural, and kinetic action tremor, especially in older adults.

The main indication for DBS in Parkinson disease is frequent motor "off" states[…] or disabling symptoms not responsive to optimal medication.

Severe shoulder abduction weakness is most likely from injury to the axillary nerve[…], which innervates the deltoid[…] muscle responsible for abduction past 15 degrees.

Serotonin syndrome presents with a triad of AMS, autonomic hyperactivity, and neuromuscular abnormalities[…] — most notably hyperreflexia and myoclonus[…].

Onset within 24 hours[…] of medication exposure is characteristic.

Key distinguishers: myoclonus + hyperreflexia[…] (serotonin syndrome) vs "lead pipe" rigidity + hyporeflexia[…] (Neuroleptic Malignant Syndrome).

Malignant hyperthermia occurs during anesthesia[…].

Fat pad biopsy[…] identifies amyloid in ~70-75% of AL amyloidosis cases and is the recommended first step when suspicion is high.

Confirmation requires tissue biopsy[…].

For focal spasticity of one arm in a child with cerebral palsy, first-line treatment is intramuscular botulinum toxin type A[…].

Oral and intrathecal therapies are reserved for generalized[…] or severe spasticity.

The best test to differentiate Parkinson disease from drug-induced parkinsonism is the DATscan[…].

Drug-induced parkinsonism: normal[…] uptake.

True PD: reduced[…] uptake.

For levodopa-induced peak-dose dyskinesias, the recommended medication is amantadine[…], which suppresses dyskinesias without worsening off periods.

COMT inhibitors block peripheral levodopa metabolism[…], thereby increasing its delivery to the brain.

MRI-guided focused ultrasound of the thalamus (specifically the ventral intermediate (VIM) nucleus[…]) is FDA-approved for treating tremor-predominant PD[…].

Dementia with Lewy bodies most often causes early visuospatial and executive[…] dysfunction — leading to repeated minor car accidents from misjudging distances.

Early memory[…] loss is less prominent.

Hallucinations in DLB are complex, well-formed[…], and often feature people (including children), animals, or insects[…] — usually occurring early in the disease.

The only FDA-approved diagnostic biomarker study for DLB is DATScan[…], which shows reduced[…] dopaminergic uptake.

Zonisamide[…] is the antiseizure medication that may benefit motor symptoms as an adjunct to levodopa in DLB.

The antiepileptic drug most commonly responsible for mild bilateral action tremor is lamotrigine[…].

Tremor of the leg[…] is more common in Parkinson disease than in essential tremor.

The most effective treatment for isolated dystonic head tremor (characterized by a null point) is Botox[…] injection — locally weakens the overactive neck muscles.

A high skull density ratio[…] favors DBS[…] over focused ultrasound thalamotomy in patients with essential tremor.

Glial cytoplasmic inclusions (hallmark of MSA) consist of misfolded α-synuclein[…] aggregates mainly in oligodendrocytes[…].

The best next step in an MSA patient with nocturnal stridor is laryngoscopy[…] to assess for vocal cord dysfunction or mechanical lesions.

A key limitation of MIBG scintigraphy in differentiating MSA from PD is overlap in early-stage PD and MSA[…] — both may show normal[…] cardiac MIBG uptake early.

MSA patients are at increased risk of developing orofacial[…] dystonia from levodopa, whereas PD more commonly causes limb[…] dystonia.

The most sensitive and specific ocular abnormality for PSP is slowed downward saccades[…] — reflecting early impairment of brainstem gaze control mechanisms.

A patient with rapidly progressive bulbar symptoms (dysarthria, dysphagia), prominent parasomnias (vocalizations/limb movements during sleep), ataxia, cognitive decline (low MoCA), and supranuclear gaze palsy → most likely diagnosis: IgLON5 encephalitis[…].

Brain MRI in corticobasal syndrome most frequently shows atrophy of the perirolandic[…] gyrus.

Axial-predominant rigidity[…] is most characteristic of progressive supranuclear palsy compared to other parkinsonian syndromes.

ARSG[…] gene variations are associated with increased susceptibility to task-specific[…] dystonia — especially writer's cramp and musician's dystonia.

Cervical MRI is most appropriate for cervical dystonia patients who do NOT have an effective sensory trick[…] — to rule out mimics such as cervical spine disease.

A three-base pair (GAG) deletion[…] in the TOR1A gene is associated with almost all cases of TOR1A-associated dystonia[…].

High-dose trihexyphenidyl[…] in children is associated with decreased[…] school performance due to cognitive side effects.

The co-occurrence of orobuccolingual and forehead chorea[…] is most characteristic of Huntington disease[…] — compared to other choreiform disorders.

The most likely cause of acute hemichorea with contralateral putaminal T1 hyperintensity[…] on MRI is nonketotic hyperglycemia[…].

The predominant motor manifestation in juvenile-onset Huntington disease (Westphal variant[…]) is parkinsonism[…] (bradykinesia and rigidity) — rather than chorea.

The most common genetic cause of Huntington disease phenocopy is a hexanucleotide repeat expansion in C9orf72[…].

A pathogenic GAA expansion (>300 repeats) in the FGF14[…] gene causes spinocerebellar ataxia type 27b[…] — typically seen in adults with slowly progressive gait ataxia, dysarthria, and visual disturbances.

First-line therapy for episodic ataxia type 2 is 4-aminopyridine[…] — decreases attack frequency and improves quality of life.

Ataxia-telangiectasia[…] is the hereditary ataxia associated with increased risk of cancer — especially leukemia and lymphoma[…].

A dry cough[…] is a systemic symptom frequently associated with CANVAS and may precede neurologic symptoms by years.

Classic tic progression involves rostrocaudal spread[…] — starting in the face/head and advancing to the trunk/limbs. This pattern differs from functional tic-like behaviors.