Movement Disorders
Parkinson’s Disease
History
• Secondary Causes – Neuroleptics, Toxin exposure, vascular disease, past encephalitis, occupation
• FHx, memory, visual complaints, swallowing, speech changes, falls
• Autonomic dysfunction – bowel, bladder, sexual function, postural dizziness, syncope
• Response to medications
Clinical Examination
“The combination of asymmetry of symptoms and signs, the presence of a resting tremor, and a good response to levodopa best differentiates Parkinson’s disease from parkinsonism.” Lang
• Early Findings – Loss of facial expression (hypomimia), decreased blink, Voice changes (hypophonia, monotonous, hesitant, stuttering, festinating speech, palilalia, echolalia), reduced arm swing, difficulty rising from chair & turning in bed, foot dystonia, anosmia, excessive greasiness of skin, stooped and shuffling gait, drooling
• Tremor – (Absent in ¼ of PD) Begins intermittently, unilaterally, worse under stress, pronation-supination, Pill-Rolling, Rest tremor, 4-6Hz, improves with posture but may be present with maintenance of posture, improves with action, spreads first to same side limbs (arm and leg) prior to opposite side, may involve chin, jaw, lips, BUT NOT HEAD (no titubation), improves with relaxation, disappears during sleep
• Rigidity – Evident during slow passive flexion-extension of large joint, made worse with activation (Froment’s sign), cogwheel represents superimposed tremor – don’t confuse with paratonia, stiff person syndrome, arthritis
• Akinesia (inability to initiate movement), hypokinesia (decreased amplitude), bradykinesia (decreased speed) – lead to slowed, decreasing amplitude movements which may halt (freezing), loss of automatic movements (hand gestures, blinking, crossing legs), micographia, hesitation in initiating movements – movements may be entrained to speed of tremor
• Postural Instability – anteropulsion and retropulsion, flexed posture, loss of righting reflexes, increased falls, abnormal Pull Test (>2 steps backward), Striatal Hand (flexed MCP, hyperextended PIP, flexed DIP, adducted thumb), Stiatal Foot (Hyperextension of great toe), arms flexed at elbows and wrist (simian posture), difficulty in rising from chair, slump into chair, falls en bloc
• Gait Abnormalities – smaller stride, gait initiation failure, festination, turning en bloc, freezing at door frames, obstacles, propulsion, spontaneous falls, NORMAL BASE
• Other feature – Hypersalivation, nocturnal drooling, autonomic disturbances (come later)
• Response to levodopa – initially in 90% of PD (MSA may initially respond)
• Atypical Features include:
o Early marked Autonomic disturbance – MSA
o Extreme flexion at neck – MSA
o Wide based, ataxic gait – MSA, SCAs
o Early marked Dementia – LBD, PSP, MSA, secondary causes
o Supranuclear Gaze Palsy – PSP
o Wide-eyed, anxious with deep facial folds – PSP
o High pitched, harsher nasal voice – PSP
o Nuchal rigidity >> limb – PSP
o Early falls – PSP
o Hyperextended posture at neck – PSP
o Oculomotor abnormalities: Slowed upward saccades, deficient vertical OKN – PSP; abnormal Doll’s eyes maneuver – PSP; Oculogyric crisis – postencephalitic PD
o Cerebellar type (intention) tremor rarely seen in PD, head titubation suggests ET, dystonic neck tremor or cerebellar tremor in eg. MS
o Cock-walk (Toe walking) – Manganese poisoning
o Extreme unilateral arm rigidity – CBD
o Apraxia, cortical sensory abnormalities, Alien limb - CBD
o Cortical Spinal Tract Dysfunction – CBD, secondary causes
o Stimulus-sensitive myoclonus – CBD and MSA
o Urinary Incontinence – NPH
• Recent 2006 AAN Guidelines – Features that suggest diagnosis other than PD:
o Falls at presentation (PSP) or early in disease course (MSA, LBD, CBD)
o Symmetry of motor findings (MSA, PSP)
o Poor response to levodopa
o Lack of tremor
o Rapid progression
o Early dysautonomia (urinary urge incontinence, fecal incontinence, urinary retention requiring catheterization, persistent erectile dysfunction, symptomatic orthostatic hypotension) (MSA)
o Levodopa Challenge Test – 250/50 acutely – improvement of UPDRS score > 30% - PD
o Olfactory function (assessed with some standard way) – PD vs PSP and CBD (but not MSA)
o MRI – features may help differentiate PD from DDx
• Recent 2006 AAN Guidelines – Features that predict rapid progression and earlier dementia in PD
o Older age at onset ?>60yrs
o Rigidity/Hypokinesia at onset (versus Tremor dominant)
o Postural instability and gait difficulty at onset
• Recent 2006 AAN Guidelines on Treatment of Neuro features of PD
o Depression – only amitriptyline shown to be effective BUT they stress that this ISN’T necessarily 1st line. Absence of evidence does not equal absence of efficacy. TCAs obviously very likely to cause S/E in PD – options would be???the usual suspects (SSRI, SNRI)
o Psychotic Symptoms – Clozapine (with usual blood work) and quetiapine NOT olanzapine
o Dementia – Donepezil and rivastigmine for PD; rivastigmine for DLB
• Hoehn and Yahr Scale for PD Disability:
0 - No visible symptoms of Parkinson's disease
1 - Symptoms on only one side of the body
2 - Symptoms on both sides of the body and no difficulty walking
3 - Symptoms on both sides of the body and minimal difficulty walking
4 - Symptoms on both sides of the body and moderate difficulty walking
5 - Symptoms on both sides of the body and unable to walk
• Non-Motor Manifestations of PD
o Pre-clinical:
Constipation
Olfactory deficit (90%)
REM sleep behavior disorder – 1/3 of PD; prior to onset in 40%
Depression
o During disease course (prevalence increases with advancing age and severity of PD)
Neuro – Depression, anxiety, psychosis, dementia (40%), delirium, apathy
Sleep disorders – REMSBD, RLS, EDS (50%), Vivid dreams, insomnia, OSA
Autonomic – the usual
GI symptoms – drooling, ageusia, dysphagia, constipation
Sensory symptoms – Pain, paresthesia, olfactory disturbance
Other – seborrhea, fatigue, weight changes, blurred vision
o Dopamine Dysregulation Syndrome
A pattern of compulsive medication use leading to disabling motor of behavioral sx
Features:
• Craving – devious or aggressive strategies to procure
• Euphoria/Mania/Dysphoria/Depression/Psychosis
• Appetitive behavior – gambling, hypersexual, binge eating, shopping
• Motor stereotypies – Punding (excessive fascination with repetitive tasks)
DDS risks include those who had premorbid addictions
DDS identified by increase use of meds beyond need, hording, etc…
Rx – Long acting DAs, strict dosing schedules, lowest effective doses
Pathology: see Pathology Notes
Pathogenesis
• Mitochodrial dysfunction
o MPTP and rotenone toxicity due to inhibition of complex I of respiratory chain, leading to energy failure and cell death
• Oxidative stress
o Excess free radicals in dopaminergic neurons due to elevated Fe levels and dopamine metabolism – leads to oxidative stress and apoptosis in genetically susceptible – also lead to TOXIC Levodopa hypothesis (as it is also converted to dopamine in these cells)
• Excitotoxicity
o NMDA overactivity leads to Ca influx and enzyme activation, generation of free radical & programmed cell death. STN known to be overactive in PD (source of overactivity)
• Neurtrophic factors – GDNF & BDNF inadequately supplied leads to cell apoptosis
• Autoimmune Hypothesis – may contribute, at least secondarily, to nigral cell loss
Environmental Hypothesis
• MPTP – acute onset PD with progression similar to PD
• Rotenone and Parquat (pesticides) – positive association in multiple studies (risk factor)
• Caffeine – protective
• Smoking – 60% lower risk of PD in smokers
• Occupational – Higher: physicians, teacher, miners, loggers – Rural living, well water drinking
Genetics
• Early Onset:
o PARK1 – AD – α-synuclein – chromo 4q – RARE – mutation leads to slower degradation through ubiquitin pathway and aggregation leading to cell death – Early onset PD responsive to levodopa – positive FHx
o PARK2 – AR – parkin – chromo 6p – COMMON – E3 ubiquitin protein ligase that tags proteins (including α-synuclein) for protein degradation – dysfunction leads to abnormal accumulation of substrate proteins and cell death – pathology has NO Lewy bodies – Mutation found in 70% of <20 onset PD, but also seen in all ages of onset (at much lower frequency)
o PARK7 – AR – DJ-1 – chromo 1p – RARE – early onset PD
o Other – PARK6, PARK9,
• Late Onset (Typical PD)
o PARK5 – AD – Ubiquitin carboxy-terminal hydroxylase L1 (UCH-L1) – chromo 4p – RARE
o Others – PARK3, PARK4 (PD/ET), PARK10
Epidemiology:
• 3% > 65 yrs; M=F; 5-10% young onset <40 yrs; Parkinsonism: 85% Idiopathic PD, 7-9% Neuroleptic Induced, 2.5% MSA, 1.5% PSP, 3% Vascular, Toxins etc very rare (postencepahlitic not since 1960’s)
Treatment
Early:
• Considerations in Initial Therapy:
o Age of Patient:
Young – Tolerate meds better but are greater risk of long-term side effects from LD
• Amantadine, Selegiline in mild PD
• DA (levodopa sparing regimen)
Old – Side effect prone, shorter life expectancy therefore less long-term side effects
• LD – 1st choice in most cases
• DA – usually as add-on in more severe cases, or where complication dictate
o Chief Complaint:
Minimal to mild symptoms – NO Rx or amantadine, selegiline
Functionally disabling symptoms – LD or DA
Specific Symptoms – Tremor – Anticholinergic
o Cost – generic LD preparations are cheapest
• Amantadine
o Likely effects mediated through NMDA antagonism; also mildly anticholinergic
o Improves (mildly) all PD symptoms and particularly improves dyskinesias
o Dosing: 100mg bid or tid
o S/E: Confusion, visual hallucinations, levido reticularis, ankle edema
o Contraindications: Renal failure
• Selegiline
o DATATOP study – effect of selegiline and Vit E on progression of disability in early PD:
Delayed need for levodopa by 9 months (later interpreted as due to a mild symptomatic benefit seen with selegiline. I.e. not a neuroprotective)
@ 3year f/u – no difference PD severity, motor complications or mortality
o Mechanism – MAOI-B Inhibitor thus blocking central metabolism of dopamine
o Dosing: 5-10 mg bid (but 2nd dose to be taken by noon – later may cause insomnia)
o S/E: Nausea, insomnia, agitation
o Contraindications: Use of SSRIs (serotonin syndrome risk), elderly
• Anticholinergics
o Thought to work due to Ach/Dopamine imbalance in striatum (Ach to much)
o Particularly effective treatment resistant TREMOR
o Dosing: Artane 1-6mg tid; Benztropine 1-6mg tid;
o S/E: Peripheral (dry eyes/mouth, urinary retention, diarrhea, blurred vision, worsening of glaucoma) Central (confusion, memory problems, hallucinations)
o Contraindications – the elderly or patients with dementia
• Levodopa
o Issues regarding use in early disease:
Response only lasts a few years – FALSE! Lasts throughout course
Earlier development of Motor Complications – LD naïve advance PD patients develop dyskinesias almost immediately (i.e. motor complications due to disease rather than the treatment); BUT motor complications MAY be related to duration of levodopa treatment – leads to use of DAs in young mild PD patients initial with rationale of delaying onset of motor complications
Possible Toxic Effect to Dopaminergic Neurons (via increased dopamine metabolism and increased oxidative stress) – likely FALSE – No convincing evidence, new evidence suggests neuroprotection; LD therapy IMPROVES SURVIVAL; No LD-related neuronal dropout in experimental animals
o Side Effects:
Acute – Nausea, dizziness, somnolence; orthostatic hypotension
• Peripheral dopa decarboxylase inhibitor used to minimize these s/e
• Carbidopa minimum or 75mg / d needed to suppress all AADC activity
Non-motor S/E
• dopamine dysregulation syndrome; vivid dreams; hallucinations; paranoid psychosis; mania; hypersexuality
Motor Complications:
• Motor Fluctuations – 50% within 5 years
o “Wearing Off” – predictable dose-time related
Most common initial problem
Mx – increase dosing frequency, substitute CR formulation, add DA, Add COMT inhibitor
o On-Off Phenomenon – unpredictable fluctuations of effect
More advanced PD, very difficult to treat
Mx - ?? Same as for Wearing Off
o Nighttime “Off” – difficult rolling in bed, muscle discomfort
Mx – same as wearing off
o Drug Failure – likely poor gastric emptying or absorption
Liquid preps, decrease protein intake, gastric motility Rx
• Dyskinesia – 70% within 5 years (rarely on DA naïve to LD) – initially may not notice mild dyskinesias, may prefer over parkinsonism, but eventually are disabling and require treatment adjustments:
o Off Period Dystonia & Early Morning Deterioration – manifests as painful foot dystonia and severe parkinsonism upon waking
Increase speed of onset of 1st levodopa effect by crushing tablet and administering with carbonated beverage
o Peak-Dose Dyskinesia – due to pulsatile dopamine at receptors
Stop selegiline / entacapone
Add Amantadine
Not on DA? – Add DA (lower LD)
On DA and LD? – Lower LD and increase DA
Change CR Sinemet to Standard Sinemet
o Diphasic Dyskinesia – occur at onset and with wearing off of effect of LD, common in young patients
Maintain constant dopamine blood levels by using high dose DA with low dose, frequent dose LD
o Dosing – Start LOW & GO SLOW
Immediate-release form: 25 mg carbidopa/100 mg levodopa one half tab PO qd; increase daily dose by one half tab per wk to initial maintenance dose of 25/100 mg tid; may increase by 1 tab qd each wk until optimal clinical response achieved
CR form: 1 tab PO qd; increase daily dose by 1 tab each wk to achieve initial maintenance dose of 25/100 mg tid or 50/200 mg bid.
CR formulation has 80% bioavailability of regular LD – therefore if converting from standard formation, increase dose by 20%
Protein meals will reduce GI absorption – leads to dosage failure, delayed effect and other motor complications – therefore avoid taking with protein meals
• Dopamine Agonists
o Affect both peripheral and central dopamine receptors; use in earlier onset PD may delay onset of motor complications with LD
o Dosing (START LOW & GO SLOW)
Bromocriptine – 15-30 mg /d divided tid or qid
Pergolide – 1.5-5 mg/d divided tid
Ropinerole – 6-24 mg/d divided tid
• Example schedule: Week 1: 0.25 mg PO tid; week 2: 0.5 mg tid; week 3: 0.75 mg tid; after week 4, if necessary, increase by 1.5 mg/d on a weekly basis up to 9 mg/d, and then by 3 mg/d weekly to total dose of 24 mg/d
• CYP1A2 metabolized – therefore increased with ciproflox and estrogens
Pramipexole – 1.5-5 mg/d divided tid
• Example schedule: Week 1: 0.125 mg PO tid; week 2: 0.25 mg tid; week 3: 0.5 mg tid; continue escalating by 0.25 mg tid each week as clinically appropriate; usual range 1.5–4.5 mg/d
• Avoid in renal failure as is excreted in urine
o S/E – NAUSEA (use peripheral dopamine blocker like domperidone), dizziness, POSTURAL HYPOTENSION, leg edema, SLEEP ATTACKs, hallucinations, psychosis, may exacerbate dyskinesias with levodopa (therefore reduce LD dose when adding DA); Ergot derivatives – retroperitoneal fibrosis, pleural effusions rarely
o Special instructions – take on full meal; advise about risk with DRIVING
o General Points: Failure of one dose not predict failure of others; switches can be done rapidly between DAs using comparable dosage; caution with use in elderly
• COMT Inhibitors (Catechol O-methyltransferase)
o Block peripheral COMT activity and peripheral L-dopa inactivation to ↑ central LD levels
o Entacapone 200mg with each dose of LD
o S/E – worsening LD s/e (nausea, drowsiness, hallucinations), orange discolouration or urine, DIARRHEA (may be severe), worsening DYSKINESIAs
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• Surgical Treatment of PD:
o Criteria for Surgery:
Typical features for PD
Failure of best medical therapy after good initial improvement
Absence of significant medical problems
Absence of cognitive impairment
Appropriate age for Sx (STN < 70, pallidal, thalamic < 80)
• Thalamotomy
o Ventral intermediate nucleus targeted
o Improves: Tremor only (occ. Rigidity and Dopa-dyskinesias)
o Side Effects: Speech and gait worsening (bil: cognitive as well)
o NOT used: does not address all PD symptoms, s/e high
• Pallidotomy (~40% improvement in UPDRS “off” state)
o Improves: Bilateral dyskinesia > rigidity and tremor
o Improves: Midline – gait and postural instability
o Improves: contralateral tremor
o Downside: Gait and postural instability improve transiently
o S/e: mild cognitive, mood effects (depression); verbal fluency, visual field defect
o Bilateral: More severe s/e including dysarthria, dysphagia
o Bad s/e: hemorrhage 1-4%, death 1 in 200
• Subthalamotomy (~70% improvement in UPDRS)
o Improves: same as pallidotomy
o Downside: same
o s/e: same, AND hemiballismus/chorea additionally
• DBS (STN or GPi)
o All the same benefits
o AND: adjust parameters to minimize the s/e, bilateral stimulation
o STN vs GPi DBS:
STN allows for dosage reduction or discontinuation of levodopa
STN efficacy maintained longer than GPi stimulation
• Bottom Line: STN is used most frequently because of best efficacy and least s/e
Last Stage PD Treatment
• Duration on LD effect becomes shorter; Dyskinesias last longer (become “Square Wave Dyskinesia – last throughout ON time) with associated myoclonus and dystonia along with chorea; Painful “Off” Dystonia occur; ON-OFF phenomenon is common; Dose failures occur;
• Medical Rx – usually polypharmacy (LD plus DA plus COMT +/- Amantadine/Selegiline)
• Associated Issues:
o Psychosis:
Reduce or eliminate – Amantadine, selegiline, anticholinergics, DAs
Consider adding – Quetiapine, Clozipine
o Dementia – 30-70% eventually develop (worsening hallucinations herald onset) – memory loss, executive function deficits, visuospatial problems – Donepezil and rivastigmine for PD
o Automomic Dysfunction:
Postural Hypotension - ↑Fluid and salt intake; Stop antihypertensives; add fludrocortisones start 0.1mg/d (mineralcorticoid leads to Na and H2O retention and elevation of BP) / midodrine 2.5 mg/d to 10 mg tid (α-agonist)
Urinary Urgency / frequency – Amitriptyline; Oxybutynin; DDAVP
Constipation – Stool softeners; ↑Fluid
Sialorrhea – Amitriptyline; BOTOX injections
Sexual dysfunction – Viagra etc…
o Depression – 50% develop – TCAs (Amitriptyline) may be good choice if associated sleep disorders, sialorrhea also; SSRIs (but avoid selegiline in this case)
o Sleep disorders:
Sleep fragmentation due to disease and dopaminergic drugs
Frequent waking due to wearing off, dystonias, nocturia
REM Behavior Disorder
• All lead to excessive daytime sleepiness
• Rx – amitriptyline and mild hypnotics
o Peripheral Neuropathy – up to 10% have dysesthesias – Rx – gabapentin
Differential Diagnosis of Parkinson’s Disease
Primary (Neurodegenerative)
o PD
o PD + (DLB, PSP, CBD, MSA)
o Other Hereditary (HD, SCA 2 & 3, Wilson’s, PKAN, Dopa-responsive Dystonia, Parkinsonism-dementia-ALS complex, Mitochondrial cytopathies
o Alzheimer’s
Secondary
o Drug Induced (D2Bs, Dopamine depletors, Li, CCBs)
o Metabolic (Hypoxia, Hypocalcemia, hypothyroidism, hypoparathyroidism)
o Mass Lesions (AVMs, tumors, etc)
o Vascular
o Trauma – dementia pugilistica
o Toxic – MPTP, CO, Manganese
o Infectious – AIDS, SSPE, Postencephalitic, CJD
Dystonia – involuntary muscle contraction causing sustained abnormal posture
Clinical Examination
• Sustained muscle contraction, causing twisting and repetitive movements or abnormal posture
• May appear as slow, twisting movement or rapid myoclonic type movements or even repetitive movements in the form of dytonic tremor – most variable movement disorder
• Direction of contraction almost always consistent; same muscles groups involved; usually becomes evident during movement (action dystonia); may be very task-specific (occupation dystonia); may be reduced of disappear with limb placed in certain position (Null Point), as opposed to myoclonus, chorea, or tremor; May be reduced by sensory tricks (Geste Antagoniste); Exacerbated by stress and fatigue; reduced by relaxation and absent during sleep. NOT PAINFUL (except cervical dystonia)
• Dystonic Tremor: Postural/action tremor as patient resembles essential tremor – mat be reduced or stop if patient relaxes limb, limb placed in position of opposition of major direction of pulling;
• Onset – In young, more likely to become generalized; onset in legs, 90% will spread and become generalized; minority with onset in cervical region spread. Hemidystonia – almost always symptomatic, lesion in contralateral putamen
Classification
• By Distribution:
o Focal
Blepharospasm – orbicularis oculi; repetitive blinking (clonic spasms), sustained closure (tonic spasms); F>M; 6th decade commonest; associated eyebrow and paranasal muscles; with oromandibular dystonia = Meige syndrome; Initial sensation of gritty eyes; aggravated by watching TV, driving, reading, fatique; Rx – BOTOX (85-95% effective)
Oromandibular – usually part of segmental dystonia
Larynx – Spasmodic dysphonia; F>M 4th-5th decade – Adductor type (common) – strained, high pitch speech, interruptions; Abductor type (Uncommon) – whispery voice; Rx – BOTOX
Cervical Dystonia – Spasmodic Torticollis; F>M, 50 – Rotational (commonest), laterocollis, retrocollis, flexion, tilting, elevation of shoulder; Tremulous type appears like ET; associated NECK PAIN (70-80%)
o Segmental – cranial, axial, brachial, crural
o Multifocal, Generalized, Hemidystonia (usually symptomatic)
• By Etiology (Ones that matter to me)
o Primary (Dystonia is only sign – may be sporadic or inherited):
Genetic Dystonias – DYT1-13 currently
• DYT1 – Early-onset primary torsional dystonia – AD (30-40% penetrance), chromo 9q, GAG triplet deletion, ATP-binding protein, Torsin A; Ashkenazi Jews; Onset mean 12.5yrs; Limb onset with spread, ultimately multifocal and generalized; marked variability in severity; Rx – initially try levodopa (in case it may be DRD); DYT1 genetic testing and counseling with FHx positive; Rx – 1st line: Anticholinergics (e.g. Artane, cogentin, Kemadrin, Benadryl, Parsidol); Baclofen, Clonazepan, Tetrabenazine; Sx – Bilateral GP stimulation – reserved for Rx failures, severe dystonias
• DYT10 – Paroxysmal Kinesiogenic Dyskinesia – Onset <20 years; intermittent attacks of dystonia, chorea, mixed; lasts <5min (most <1min); triggered by sudden movements; no LOC; frequency – many per day (most) to few per year; May be symptomatic (MS, vascular, glucose or Ca disorders); Most hereditary with +FHx; idiopathic – no known gene yet; Rx – CBMZ or PHT very effective at typical doses
• DYT8 – Paroxysmal Non-kinesiogenic Dyskinesia – Onset in childhood; intermittent attacks of chorea, dystonia, athetosis, balismus; triggered by stress, coffee, fatigue, EtoH, menstruation; last 10min to hrs; few per year to many per day; gene recently discovered – NOT a channelopathy; Rx – benzos may help; AEDs DO NOT WORK
Sporadic – include all adult onset focal and segmental dystonias
o Dystonia-Plus syndromes:
Dopa-Responsive Dystonia (Segawa syndrome)– DYT5; GTP cyclohydrolase I deficiency, chromo 14q, AD (AR form); Begins in early childhood, generalized or segmental dystonia; DIURNAL variation, with worsening throughout day; improved after nights sleep; PARKINSONIAN features (rigidity, bradykinesia); Rx – 100% have marked and sustained response to 600mg / day Sinemet – considered diagnostic in appropriate clinical setting
Myoclonus-Dystonia (Essential Myoclonus) – DYT11; AD; chromo 7q; ε-sarcoglycan; dramatically alcohol sensitive myoclonic jerks in dystonia affected or unaffected regions; begins in 2nd decade; dystonia in necks or limbs; myoclonus affects face, proximal muscles and truck; non-progressive; variable severity
o Secondary Dystonia (+weakness, amyotrophy, spasticity, ataxia, ocular abn, cognitive, sz)
AD – Huntington’s; SCA3; Other SCAs; DRPLA; Farr’s Disease
AR – Wilson’s; PKAN deficiency; Gangliosidoses; Leukodystrophies; Other inborn errors of metabolism; Neuroacanthocytosis; Parkin mutations
X-linked – Lubag (DYT3 – X-linked dytonia and parkinsonism)
• Filipino Males, 5th decade, progressive dystonia with parkinsonism, poor response to medication, death in 10-12 years
Mitochondrial – MERFF, MELAS, Leber’s
Acquired – CP, Infectious, Trauma, CPM, APLA syndrome, Stroke, Tumor, MS, SC injury, PNS lesion, DRUGS: Neuroleptics, Dopamine receptor AGONISTS
Dystonia with Parkinsonism – PD, PSP, MSA, CBD
Investigations
1. Diagnosis based on History and Physical in most cases (sporadic focal dystonias)
2. Everyone gets:
o Serum ceruloplasmin, serum copper, 24 hour urine copper (r/o Wilson’s as Rx disease)
o Brain imaging plus cervical MRI – r/o structural causes
3. In special circumstances:
o Labs – ANA, ESR, APLA testing, CBC, electrolytes, renal and liver studies (special labs for various specific etiologies in selected individuals)
o Biopsy, CSF testing in specific contexts – see continuum
General Treatment Guidelines
1. BOTOX Injections – for most focal and segmental dystonias
o BOTOX B – acts by cleaving synaptobrevin (SNARE protein) in presynaptic Motor End Plate, thereby blocking NT release, causing muscle weakness – side effects include excessive weakness (dysphagia in cervical dytonia), formation of blocking antibodies in 5-20%, if occur may use alternate serotypes of BOTOX (A-G exist) – contraindications (relative) include – pregnancy, lactation, NMJ disorders, MND, use of aminoglycoside
o Currently licensed for use in: cervical dystonia, blepharospasm, hemifacial spasm, strabismus – often used off-label for other dystonias
2. Oral Medications – for all multifocal, generalized and segmental dystonia
o Levodopa – to be tried in all childhood onset dystonia – effective in DRD
o Anticholinergics – most effective meds – 40-50% get good effect
Artane (Trihexphenidyl) – 2.5mg OD starting; increase up to 100-120 mg/d
o Baclofen – start 10mg qhs, increase to 30mg tid
o Clonazepam – start 0.25 qhs, increase to 1mg qid
o Tetrabenazine – particularly effective in Tardive Dystonia
3. Surgery:
o Deep Brain Stimulation – Globus Pallidus
o Denervation with ramisectomy, rhizotomies, myomectomies (last resort)
Chorea – irregular, unpredictable, random, jerky movements that flow from one body part to another or a complete inability to sustain a steady body position
Huntington’s Disease
History
• May come to attention due to Motor (clumsiness or dysarthria), Personality changes (irritability or apathy), Cognitive deterioration (Poor judgement, inability to continue work, driving problems)
• Patient’s often unaware or unconcerned with early signs
• Family history either positive; negative – ask about unknown paternity, suicide, history of psychiatric disorder, early demise; 6-8% have NO FHx – are new expansion into mutant range from pre-mutation
Clinical Exam (Huntington’s) – Motor, Personality and Cognition
• Earliest features: Motor signs at onset in 60%, Behavioral signs in 15% and Both in 25%; patient appears restless and fidgety, explosive dysarthria (chorea affecting diaphragm) – often not noticed or denied by patients – movements are incorporated into volitional movements (PARAKINESIA)
• MOTOR IMPERSISTENCE (inability to continue ongoing movement, manifests as dropping things, dipping at knees while walking, Darting tongue (tongue can’t be held out consistently), Milkmaid’s Grip (can’t maintain continuous hand grip));
• Speech is slurred, interrupted, and produce simple vocalizations (grunts and humming), mutism
• Occulomotor: Slow initiation and speed saccadic eye movements, Saccadic smooth pursuit, poor OKN
• EPS: initially hypotonic and hyperreflexic – then becomes bradykinesia, rigid and dystonia as disease progresses
• Abnormal gait – Marionette-like – wide-based, lurching, dipping, bobbing, falls
• Dysphagia – weight loss, aspiration ultimately leads to death
• Juvenile Onset (<21 yrs) – Dystonia and Parkinsonism common, whereas chorea uncommon; seizures and myoclonus seen
• Personality and Affect: Irritability (commonest and earliest); apathy, rigid thinking; Mania or depression (38%); Psychosis uncommon; Suicide ideation common (7.5% of deaths)
• Cognition: Dysexecutive syndrome (frontostriatal degeneration) earliest; Verbal dysfluency, Eventually global severe dementia at late stage
Pathology – see Pathology Notes
• Functionally, initial loss of neurons striatum indirect pathway of basal ganglia – leads to decreased inhibition of GPe – increased inhibition of STN – decreased stimulation of GPi/SNr – therefore increased activity of thalamocortical pathways and increased movements – as disease progresses, degeneration of direct pathway leads to decreased chorea and increased parkinsonism, akinesia
• Pathogenesis: Mutant huntingtin has large PolyQ tracts which is resistant to degradation – thereby forming ubiquinated cytoplasmic and intranuclear aggregates that may lead to dysfunction via:
o Interference with cellular proteins
o Gene transcription dysfunction
o Axonal transport dysfunction
o Oxidative stress
o Mitochondrial dysfunction
o Apoptosis activation
Investigations
• Genetic Testing – in appropriate context is all that is needed to make diagnosis
• Imaging – MRI often shows atrophy of caudate and putamen
• Secondary causes – Labs: electrolytes, TSH, renal studies, APLA, ANA, dsDNA, glucose; Imaging: MRI – structural lesions, PANK2; Hx of drug use, toxin exposure
Treatment
• Chorea Therapy:
o Neuroleptics – Quetiapine, Respiradone, Olanzapine, Clozapine
o Dopamine Depleting Agents – Tetrabenazine, Reserpine
o Benzodiazepines – Clonazepam
o Glutamate Anagonists – Amantadine
• Depression – SSRIs, TCAs
• Irritability – SSRIs, AEDs (VPA, CBMZ)
• Non-Rx: Physiotherapy, Occupational Therapy, Home Care, Social Work
Classification
1. Hereditary AD
a. Huntington’s Disease
b. Benign Hereditary Chorea – onset in young (1st decade), nonprogressive chorea with mild cognitive and behavior changes, delayed milestones; chorea improves with aging; genetically heterogenous – Rx – symptomatic
c. Familial Paroxysmal Kinesiogenic and Dystonic Choreoathetosis
d. DRPLA – Onset in 3rd decade; Common in Japan only; Chorea, Ataxia, Myoclonus, Seizures (PME), dystonia, parkinsonism, psychosis and dementia – death in 20yrs; CAG trinucleotide repeat disorder with anticipation from paternal inheritance; Chromo 12;
2. Hereditary AR
a. NCL
b. Wilson’s Disease (see below)
c. Niemann-Pick, Lesch-Nyhan Disease
d. Hallervorden-Spatz disease – early onset (infancy) delayed motor development, then EPS: dystonia, muscle rigidity and spasticity, choreoathetosis; progressive cognitive decline; progressive course until death in childhood or early adolescence; Other features include: dysarthria, dysphagia, bilateral retinopathy (RP), optic atrophy, seizures; Late-onset presents with slowly progressive chorea without dementia – Labs: acanthocytosis; MRI: “eye-of-the-tiger” sign – low signal intensity ring surrounding high signal intensity in globus pallidus; Pathology: Iron deposition in Basal Ganglia; Genetics: PANK2- panthothenate kinase, chromo 20p, AR; Rx – Levodopa, Anticholinergics, Baclofen, BOTOX, Seizure control; DDx Wilson’s, NCL, Junvenile Huntington’s Tay Sach’s
3. Other Neurogenerative Choreas:
a. Neuroacanthocytosis – group of disorder with spiny acanthocytes in the peripheral blood
• AR Neuroacanthocytosis – chromo 9 CHAC gene – onset 30’s oral chorea, dystonia causing involuntary biting of lips, tongue and buccal surfaces. Other features: behavioral changes like HD; subcortical dementia; myopathy with elevated CK; axonal neuropathy
• The McLeod Syndrome – X-linked recessive – XK gene – onset 50’s; slow progression; Features – axonal neuropathy; limb and oral chorea; facial tics; late subcortical dementia and behavioral changes
b. Farr’s Disease – bilateral calcification of basal ganglia and subcortical WM; 2/3 symtomatic – ½ with MD’s including chorea, parkinsonism, others. Cognitive, cerebellar, pyramidal, psychiatric findings occur. Basal ganglia calcification VERY NON-SPECIFIC – occur in normals, and after CNS infections, metabolic and genetic condition
4. Autoimmune
a. Sydenham’s Chorea – months after rheumatic fever, appearance of insidious onset generalized chorea, F>M, evolves over weeks, recedes in months. Associated: dysphoria, restlessness, irritability, OCD symtoms; Pathogenesis – anti-basal ganglia Abs directed against streptococcal and striatal antigens (molecular mimicry); Rx – 1st: VPA and CBMZ, 2nd: Neuroleptics: Chorea may recur later with OCP, pregnancy.
b. Chorea Gravidarum – usually occurs in context prior Sydenham’s
c. SLE – 1% of patients, 2% with neuropsychological manifestations
d. Anti-Phospholipid antibody Syndrome
e. MS, PAN, Behcet’s
5. Neoplasia – either local basal ganglia involvement of paraneoplastic (anti-Hu and CRMP)
6. Vascular – Infarct, AVM
7. Infection – blah blah blah
8. Metabolic:
a. Nonketotic Hyperglycemia – common cause of hemichorea / hemibalismus
b. Electrolyte disorders: hypo/hypernatremia, hypoCa
c. Endocrine disorders: Hypethyroid, Renal Failure, Hypoparathyroid, Thiamine def
9. Toxins: Alcohol, CO, Manganese, Mercury, Thallium, Toluene
10. Drugs:
a. Neuroleptics – Tardive Dyskinesia (see below)
b. Dopaminergic medications in PD – dyskinesias
c. Anticonvulsants – Dilantin, Lamotrigine, Gabapentin
d. Cocaine and Amphetamine – “Crack Dancing”
Tremor – rhythmic, involuntary, oscillatory movement of a body part
Phenomenology
1. Rest Tremor – must be completely supported against gravity
2. Action Tremor
a. Postural Tremor – while maintaining position against gravity
b. Kinetic Tremor – during any voluntary movement
i. Simple Kinetic
ii. Intention Tremor – increases in amplitude with visually guided movements towards the target at the termination of the movement
iii. Task-Specific Tremor – e.g. primary writing tremor
iv. Isometric Tremor – with muscle contraction against a stationary object
Syndromic Classification
1. Essential Tremor – most common MD – 4% of elderly
a. Core Criteria:
i. Bilateral action tremor of the hands and forearms (but not rest tremor)
ii. May have additional or isolated head tremor with no signs of dystonia
iii. Absence of other neurological signs except cogwheel phenomenon
iv. Secondary: Long duration (>3yrs), Positive FHx (17-100%), EtoH improves
b. Red Flags:
i. Unilateral tremor, leg tremor, rigidity, bradykinesia, rest tremor = PD
ii. Gait disturbance = PD or cerebellar tremor
iii. Focal tremor = dystonic tremor
iv. Isolated head tremor = dystonic tremor
v. Sudden or rpaid onset = psychogenic or toxic tremor
vi. Current drug treatment that may cause tremor = drug induced of toxic tremor
c. The facts: 4-12Hz tremor; flex-ext wrist; may start one side, always becomes bilateral, but may be worse on one side; rest component present with severe action tremor; NO pause when patient raises hands from rest cf. PD where change position there is a short halting of the tremor; handwriting remains large; head tremor yes-yes or no-no; onset mostly in older age, may be onset in 20’s; tremor aggravated by stress, fatigue, drugs
d. Variants –
i. Orthostatic tremor – subjective feeling unsteady while standing; 13-18Hz fine amplitude tremor in legs while stranding – need EMG; Rx – Clonazepam
ii. Primary Writing Tremor – 5-7Hz only during writing; may dystonic tremor
iii. Isolated Voice, Tongue, Chin tremor
e. Pathology: Unknown – but likely cerebellar and inferior olive oscillators as generators and thalamus involved in maintenance
f. Investigations – NONE – Archimedes spiral to follow progression over time
g. Rx: (not effective for head or voice tremors)
i. Primidone – ¾ have 40-50% improvement (RCTs) – 25mg qHS then SLOW titration by 25mg increments to 250g/d – S/E – sedation, vertigo, nausea, unsteadiness (resolve with continued use)
ii. Propranolol – symptomatic benefit in 50% - reduces tremor amplitude – Start 20-40mg/d increase to MAX 360mg/d; CONTRA – asthma, CHF, 2nd or 3rd degree heart block, DM; S/E – Fatigue, orthostatic dizziness, nausea, depression, diarrhea, impotence, rash (uncommon and mild usually)
iii. Other – Benzo’s (alprazolam), BOTOX (weakness), Topiramate, Clozapine
h. Sx: VIM DBS – 80-90% effective, bilateral is safe; VIM thalamotomy (S/E dysarthria, cog impairment, numbness mild)
2. Dystonic Tremor – 4-7Hz; irregular amplitude and frequency either in area affected by dystonia (Dystonic tremor), or in other area (Dystonic-associated tremor); not normally seen during complete rest; aggravated with movement in opposite direction of dystonic muscle; Rx – BOTOX
3. Parkinson’s Tremor – Rest tremor; 4-6Hz; may have postural or simple kinetic component; abates with purposeful movements; Rx – Levodopa, Anticholinergics; Sx – Subthalamic DBS
4. Cerebellar Tremor - <5Hz; Intention tremor +/- postural, +/- Head titubation, but NO REST; MS most common etiology; associated dysmetria, hypotonia, dyssynergia; Rx – sucks, VIM DBS
5. Holme’s Tremor (Rubral Tremor) - Irregular rest, intentional and occasionally postural tremor; Rate of 4.5hz (i.e. SLOW); Not as regular as other tremors; Occurs as late 4 wks to 2years after lesion occurs; lesion in the midbrain, red nucleus or thalamus; Rx sucks – VIM DBS
6. Palatal Tremor – Rx sucks
a. Essential – Ear Click – Tensor Veli Palatini affected – no olivary hypertrophy
b. Symptomatic – No click – Levator Veli Palatini – may affect EOMs, face and extremity muscles – lesion in Guillain-Molleret Triangle (Inferior Olive, central tegmental track, red nucleus, ICP and SCP, dentate nucleus) – associated olivary hypertrophy
7. Drug Induced / Toxic Tremor – of any type (enhanced physiological with sympathomimetic drugs, rest tremor with neuroleptics) – need history of use
8. Neuropathic Tremor – typically irregular postural/kinetic tremor; demyelinating neuropathies
9. Psychogenic Tremor – Criteria:
a. Sudden onset or remission
b. Unusual combos of rest, postural and intention tremor
c. Distractibility (variation in amplitude and frequency with distraction)
d. Entrainment
e. Coactivation Sign – resistance to passive movement of limb due to coactivation of antagonist muscles
f. Somatization in PMx; Other unrelated neuron findings; weight bearing increases amplitude; improves with psychotherapy; increases with attention
10. Physiologic and Enhanced Physiologic – 8-12Hz – worsened by hyperthyroid, hypoglycemia, caffeine, smoking, drugs
11. Fragile X Premutation Syndrome – Male; 50’s’ gradual onset intention tremor; later development of truncal and gait ataxia, +/- loss of sensation in lower extremities, autonomic dysfunction; short term memory loss and executive dysfunction with gradual progression to dementia; MRI show hyperintesity in MCP; mechanism – gain of function toxic effect of excessive CGG containing FMR1 mRNA forming neuronal inclusions;
Wilson’s Disease
• AR; chromo 13; ATP7B gene – copper transporting adenosine triphosphatase – over 200 mutations
• Increased hepatocellular Cu – oxidative stress and cell death
• Two types of presentations
o Hepatic (40%) – childhood onset – fulminant hepatitis to chronic hepatitis and cirrhosis
o Neurological (40%) – adulthood onset > 20: MDs typically:
Tremor – any kind, often asymmetric (but proximal wing beating must be classical)
Dysarthria ("whispering" dysphonia), drooling, incoordination, gait disturbances, clumsiness,
Generalized dystonia, of face = “risus sardonicus”
Parkinsonism
o Behavioral / Psychiatric (15%) – Temperament problems (tantrums), cognitive impairment (failure at school, work), Psychosis
o “Pseudosclerotic” Phenotype – ataxia at onset with MS type lesions on MRI
o Occular – Kayser-Fleischer Rings (Cu in Descemet’s membrane), sunflower cataracts
o Other – Renal calculi, renal failure; Skeletal – rickets; Hemolytic anemia
• KEY POINT – any patient <50 years presenting with MD of ANY type (particularly dystonia, parkinsonism, and ataxia) as well as dysarthria, should be screened for Wilson’s
• Pathology – Impaired biliary elimination of excess Cu from diet due to defective gene product– free Cu accumulates in tissues, levels are high in urine – free Cu is toxic to cells – Ceruloplasmin also fails to be transported out of liver – levels are low in serum
• Screening:
o Serum ceruloplasmin – False – in 5%; False + in heterozygotes, liver disease
o Raised Urine Free 24hr Cu – Best test (100% sensitive) but False + in cholestasis
o KF Rings – almost 100% in neurological or psychiatric presentation – presence in the context of symptoms suggestive of Wilson’s is ENOUGH to make diagnosis
o Liver biopsy – GOLD Standard – but false + liver disease with cholestasis
• MR – bright signal on T1 and T2 in the basal ganglia (caudate and lentiform nucleus)
• Rx –
o Initial Presentation – Tetrathiomolybdate decoppering treatment for 8 weeks – forms three way complex between protein, Cu and itself, detoxifying it, and prevents absorption – fast acting; S/E – mild reversible anemia
o Maintenance – Zinc acetate 50-200 mg tid – induces intestinal cell metallothionein which binds Cu preventing absorption into circulation – excreted as cells sloughed; S/E – GI discomfort, must take on empty stomach – very effective
o D-Penicillamine – chelator, increases urinary excretion of Cu;
S/E –
• Initial neurological (irreversible) worsening as Cu is mobilized from tissue stores (50% risk with 50% never recovering)
• Acute hypersensitivity reaction – rask, hives, fever (25-30%)
• Bone marrow suppression
• Chronic toxicity to skin
• Induces autoimmune disease (MG, SLE, Goodpasture’s)
Myoclonus – sudden brief, shock-like involuntary movement caused by muscle contraction of inhibitions
• Classification
o Clinical Presentation
Distribution (Focal, Segmental, Multifocal, Generalized)
Relation to Activity (Spontaneous, Reflex, Action)
Pattern (Rhythmic, Irregular, Repetitive or Oscillatory)
o Anatomic Origin
Cortical – Brief (10-30ms) EMG burst; one body region; muscles activated in rostral to caudal sequence; Time-locked cortical event by back averaging precedes jerk; GIANT SSEPs (exp with reflex myoclonus)
Subcortical (Reticular) – has NONE of the above features; more generalized; begins in trapezius then travels UP brainstem and DOWN spinal cord at same time
Segmental (Spinal or Brainstem) – Spontaneous and rhythmic; NO EEG correlate, NO large SEPs, NOT stimulus sensitive; persist during sleep; Usually lesion in brainstem or spinal cord causing loss of local inhibition; e.g Palatal myoclonus.
Propriospinal – usually idiopathic; rhythmic or not; begin mid-thoracic spreading up and down affecting axial muscles; may be worse lying down; spontaneous or stimulus evoked; EMG long duration 150-300ms
Peripheral Nerve or Root
o Etiology
Physiologic – hiccups, hyponogogic jerks, benign neonatal myoclonus, anxiety
Essential – Sporadic, Hereditary (see Dystonia-Myoclonus above)
Epileptic – see epilepsy notes
Symptomatic – huge differential (bold – myoclonus typical feature)
• Storage Diseases (PMEs e.g. Lafora, NCL, Tay-Sach’s)
• Spinocerebellar Degeneration (Ramsy Hunt Syndrome, Fredreich’s, AT)
• Basal Ganglia Degen’s (Wilson’s, CBD, PKAN, PD, PSP, etc)
• Mitochondrial Encephalopathies
• Dementia’s (CJD, Alzheimer’s)
• Viral Encephalopathies (SSPE, HSV etc.)
• Metabolic (Liver, renal, electrolyte, glucose)
• Toxic (TCAs, levodopa, heavy metals, narcotics, AEDs, CCBs, many other)
• Physical encephalopathies (Post-anoxic Lance Adams, trauma etc.)
o Lance Adams – anoxic brain injury with coma – after recovery develop voluntary movement induced severe generalized myoclonus that also affects gait (negative and positive) resulting in falls. Pathology – decreased serotonin metabolites in CSF, GABA involved; Rx – VPA and clonazepam 1st line Levetiracetam
• Focal CNS damage
o Pathophysiology – disordered serotonin and GABA systems are thought to play a role
o Investigations –
Hx (toxins, drugs, FHx, anoxia etc.);
Labs – electrolytes, Cr, BUN, Ca, glu, LFTs, Toxicology screen
Imaging – if segmental myoclonus for sure, otherwise depends on hx, exam
EEG, SSEPs in certain circumstances (Giant SEPs in cortical myoclonus)
Surface EMG – pattern of spread, duration of burst (<70ms organic, >70ms may be psychogenic esp. with 1 sec back-averaged Bereitschaftpotential)
Other tests for specific diagnoses as needed (e.g Wilson’s)
o Rx:
Cortical Myoclonus - VPA, clonazepam, primidone, 5-HTP plus carbidopa (serotonin precursor – n/v, diarrhea, abdo pain, hypotension – not easy to tolerate)
Reticular Myoclonus – VPA, clonazepam
Spinal myoclonus – 1st: clonazepam, 2nd: Valium, CBZ, Tetrabenazine
Tics
• stereotyped, repetitive, non-rhythmic, jerk-like movements that are “semi-voluntary”
• May be rapid (clonic) or sustained (dystonic)
• Preceded by SENSORY URGE temporarily relieved by tic
• SUGGESTABILITY – will perform tics upon suggestion
• Suppression by DISTRACTION
• VOLITIONAL CONTROL – for short time will buildup of urge to perform tic
• Simple Tics: Motor (eye blinks, rolling, shoulder shrugs) and Vocal (sniffs, grunts etc.)
• Complex Tics: Motor (touching, hitting, echopraxia, copropraxia) Vocal (echolalia, palilalia, coprolalia in 10% if GTS)
• Primary:
Gilles de la Tourette’s Syndrome
• Criteria:
o Both Multiple Motor AND one or more Vocal tics present at SOME time during illness
o Tics occur many times per day for > 1 year
o Tics changing over time (location, number frequency, type, complexity, severity)
o Onset < 21 years old
o Tics witnessed by reliable examiner and recorded visually
o No other medical condition present that may explain tics
• Behavioral Abnormalities :
o Obsessive Compulsive Disorder – 45-63% (seen in female relatives of GTS patients)
o Attention Deficit Disorder – 50-75% (or ADHD – may lead to learning diabilities)
o Other – anxiety, phobias, mania, depression
• M>F; 0.1-3% prevalence in children (5-19% have motor tics); mean age onset 6-7yrs; facial twitching onset in 50-70%; tics progress over time from simple to complex; prepubertal worsening, postpubertal improvement, stabilization in adulthood; 50% resolve by 18yrs; exacerbated by certain situations (stress, emotion, TV watching, etc.); 20% Tics DO NOT stop in SLEEP (cf other movement d/o)
• Pathology: ?unknown – MRI volumetric: smaller volume of caudate and lentiform nucleus; Functional Studies: hypoperfusion in various brain regions including basal ganglia and frontal regions; abnormal corticostriatothalamocortical circuitry that prevents unwanted movements from being suppressed; Dopamine likely plays a primary role (although no gene related to dop abn);
o Immune hypoythesis – PANDAS (pediatric autoimmune neuropsychiatric disorder with streptococcal infection) - criteria
Presence of OCD or tic
Prepubertal onset
Sudden onset or episodic symptoms
Temporal association between infection and neuropsychiatric exacerbations
Associated neurological abnormalities
• Genetics – 8% dizygotic and 53% monozygotic twins are concordant – polygenetic inheritance – major gene is likely AD with variable penetrance; no gene locus thus identified
• Rx:
o Tics
Atypical neuroleptics (1st line) – mostly the same side effects except less tardive
Typical Neuroleptics (Pimozide, Haldol); S/E QT prolongation, tardive dyskinesia, acute dystonic reactions, parkinsonism, weight gain, gynecomastia, sedation
Tetrabenazine – s/e Depression, sedation, akathesia, nausea, anxiety
α2-agonists (Clonidine, guanfacine)
Low Dose Pergolide (RCT) – may act on D1 presynaptic autoreceptors to reduce dopamine release – 0.15-0.45mg / day
o ADHD – Ritalin, Adderal, atomoxetine (Strattera)
o OCD – SSRIs (fluoxetine)
• DDx:
o Transient motor or vocal tics of childhood (< 1 yr)
o Inherited Tics:
GTS ● HD ● Neuroacanthocytosis,
HD ●PKAN ●Tuberous Sclerosis ●WD
o Secondary Causes:
Infections (PANDAS, viral encephalitis, HIV, Lyme, Syphilis)
Drugs (neuroleptics, amphetamines, cocaine, Ritalin, AEDs)
Toxins (CO)
Developmental (MR, static encephalopathies, Autism)
Chromosomal (Down’s, Kleinfelters, Fragile X)
Drug Induced Movement Disorders
Early and Acute Reactions
1. Acute Dystonic Reaction (D2Bs Typical >> Atypical)
1. 50% < 48hrs, 90%<5d; 3-10% of exposed patients; young>>old (15x); M>F;
2. Torticollis > glossal dystonia > Trismus > Oculogyric Crisis > Opisthotonus
3. fluctuates; more generalized young; +FHx;
4. Typical>Typical neuroleptics; Antiemetics (All D2 receptor blockers)
5. Rx: 2mg IV benztropine STAT q15min to MAX of 6mg followed by Oral Benztropine q6h X 48hrs (longer if antipsychotics must be continued); stop offending agent if possible; Other options are benzos or Amantadine
2. Oculogyric Crisis (type of acute dystonic reaction)
1. Prodrome: restlessness, fixed stare followed by:
2. Sustained upward eye deviation, retrocollis, open mouth, tongue protrusion; agitation
3. Onset < 72 hrs with Rx initiation, elevation, change to IV
4. May be recurrent – triggered by anxiety
5. Associated conditions: Post-encephalitic PD, juvenile PD, GTS, MS, Neurosyphilis, HSV
6. Meds associated: Neuroleptics cause; Levodopa, Li, TCAs, SSRIs, MAOIs, CCBs can trigger recurrence?
7. Rx – Benztropine mg IV IV or IM or Benzos; Recurrent: Amantadine maintenance
3. Drug-Induced Parkinsonism (D2Bs, Tetrabenzazine, CCBs, SSRIs, VPA, Li, amiodorone)
1. 15% prevalence; F>M; old>young;
2. Onset (Early) < 3 months in 90%; On CCBs < 9-12 months
3. Clinical: Indistinguishable from Classical PD (BUT <tremor, no cogwheeling, more symmetric, Rabbit Syndrome = oral-facial-nasal tremor in 3%)
4. Prognosis – 66% recover in 2mo; some require > 6mo; 16% remain PD (likely had PD)
5. Rx: ↓ Dose, ↓ potency, 1st line: Anticholinergics (Atrane); 2nd Amantadine; 3rd L-dopa
4. Acute Akathisia (inability to sit still) – (D2Bs, AEDs, Benzo withdrawal, Li, CCBs)
1. Hx: RESTLESSNESS and an INNER URGE TO MOVE
2. You see STEREOTYPIES: excessive voluntary movements (pacing, rocking, weight shifting, foot or hand tapping, vocalizations)
3. Distraction improves (like Tics); Lying down improves (Unlike Tics)
4. Onset with days; 90% prevalence with neuroleptic Rx; young=old, M=F
5. Path: Blockade of MESOCORTICAL dopaminergic tracts
6. Differentiate from Tardive Akathesia (increasing Neuroleptic HELPS vs Worsens)
7. Rx: Decrease dose neuroleptic; lower potency; Propranolol (30-60mg/d); Clonidine; benzos; amantadine;
8. NOTE: Long-term anticholinergics thought to increase risk of Tardive Dyskinesia
5. Neuroleptic Malignant Syndrome (D2Bs, levodopa withdrawal)
1. Triad: Autonomic Dysf (100%), Extrapyramidal Signs (90%), Cognitive Changes (70%)
2. 0.5-1% incidence; D2 blocking agents, rapid withdrawal of levodopa; occurs early in course (days), but may occur at any time
3. RFs: Dehydration, Hyponatremia, Young, Brain Injury, Li therapy, depo formulations
4. Criteria (DSM): Increased TEMP and RIGIDITY plus 2 or more:
Diaphoresis ▪ Tremor ▪ Dysphagia ▪ Altered mental status
Tachycardia ▪ Incontinence ▪ Labile BP ▪ ↑ WBC ▪ ↑CK
5. Other: Seizures, stupor, coma – Mortality 5%
6. Path: Central dopaminergic dysfunction in BG and Hypothalamus; muscle membrane dysfunction, sympathetic nervous system dysfunction (???)
7. Rx:
1. Discontinue offending Meds
2. Supportive – HYDRATION, cooling
3. Dantrolene 3-5mg/day divided tid IV until symtoms improve (liver toxicity)
4. Bromocriptine 5mg qid x 10d
5. Options: Levodopa, benzos, pergolide, amantadine, ECT
6. Drug-Induced Chorea – see continuum and PD section above (Levodopa dyskinesias)
7. Drug-Induced Myoclonus – see continuum
8. Drug-Induced Tics – see continuum
Late and Persistent Reactions
9. Tardive Dyskinesias (D2Bs >> TCAs, SSRIs, AEDs, Li)
i. Withdrawal Emergent Dyskinesias
a. Reduction or rapid withdrawal of D2Bs within 2 weeks; 20% children; generalized choreoathetosis, tongue protrusion, chewing, torticollis; IMPROVES within 2-3 mo
ii. Tardive Stereotypies (Tardive Dyskinesia)
a. Stereotypy = Involuntary, coordinated, patterned, repetitive, ritualistic movement or utterance which occur in:
Autism ▪ MR ▪ RLS ▪ Rett Syndrome ▪ 14% schizophrenics ▪ 1-4% elderly
b. Classic: Oro-bucco-linguo-masticatory; chewing, lip smacking, “Fly catching” (tongue protrusion), Tongue movement in floor of mouth (“Bonbon sign”) – are WORSENED by distraction (cf Tics), Improve with tongue protrusion (cf HD)
c. Less Common: Pelvic rocking, abdo movements, Vocal (humming, moaning, resps)
d. Prevalence: 25%, Much greater incidence in AGE > 50 (4-5% / year in young)
e. RFs: AGE, F>M, affective d/o, organic brain disease, depo Rx, Anticholiergic Rx; Pharmacogenomics – heterzygote mutants of CYP2D6 alleles increased risk, certain dopamine D3 receptor subtype increased risk
f. Criteria (DSM): Minimum 3 mo D2Bs exposure (1 mo if > 60)
g. Pathophysiology (various theories, none correct:
i. Striatal Dopamine D2 receptor supersensitivity (sensitivity occurs before TS, don’t resolve, don’t occur with Dop depletors, and don’t always occur)
ii. Destruction of striatal GABA neurons
iii. D2Bs induce free radical formation and cytotoxic damage (Vit E shown to NOT work in RCT, but still used)
iv. Induced changes in glutaminergic transmission (increased)
h. Rx: MAY BE REFRACTORY
i. 1st: Tetrabenazine (50% effective) – 25mg upto 150mg / d divided bid or tid (S/E - drowsiness, PD, Depress, hypotension, anxiety, insomnia, akathesia)
ii. Clonazepam, Quetiapine, Clozapine, BOTOX (focal), Vitamin E others
iii. Restart antipsychotic at HIGHER dose, Surgery
iii. Tardive Dystonia
a. Less common; More disabling, Less remission (10-20%), earlier onset
b. Improves with ACTION (cf primary dystonia), NO sensory tricks work, ATTENUATES with distraction
c. Rx: Anticholinergics improve 45%, Tetrabenazine, BOTOX
iv. Tardive Akathesia – similar to acute form but Rx like TS
v. Tardive Myoclonus/Tics/Tremor – rare but do occur
Hemifacial Spasm
• Unilateral, involuntary, arrhythmic, tonic or clonic intermittent spasms of orbicularis oculi that gradually involves lower facial muscles of CN VII
• Contractions may be exacerbated by stress, anxiety or nervousness
• May have audible click (stapedius), mild facial weakness eventually
• Same pathology as Trigeminal neuralgia
• Lesions: Anywhere along course of nerve from nucleus (typically vascular loop)
• Rx – BOTOX (1st) ; AEDs (2nd)
• Differentiate from Blepharospasm:
o Involuntary, spasmodic, forceful contraction of orbicularis oculi
o Always Bilateral and Symmetric
o May be present with other EPS signs (e.g PD, Tardive etc.)
o May involve other muscles (Meige Syndrome: Blepharospasm plus oromandibular dystonia)
Stiff Person Syndrome
• Clinical:
• RIGIDITY and MUSCLE STIFFNESS usually symmetrical with prominent axial and proximal limb involvement leading to excessive LUMBAR LORDOSIS – stiffness FLUCTUATES in severity throughout day – may be absent during sleep – begins insidiously (one limb = stiff limb syndrome) then progresses slowly over years
• Painful muscular SPASMS elicited by touch, startle or emotion, or spontaneous
Usually involves axial (extension of truck) and extension of legs (prox limbs)
Typically begin with myoclonic jerk followed by tonic spasm lasting seconds
Autonomic effects during spasm include Diaphoresis, tachycardia, ↑BP ↑temp
May lead to sudden death in 10%
• Other features – hyperreflexia, exaggerated startle, paroxysmal fear, sudden falls (spasms
• Associated conditions – IDDM (30-60%), autoimmune thyroid disease, pernicious anemia, vitiligo
• EMG –
• continuous motor unit activity (despite attempts at relaxation); lessen with sleep/anesthesia
• Exaggerated and spreading of exteroceptive reflexes – stimulate a peripheral nerve and get fast (spinal reflex) myoclonic burst followed by tonic increase in motor unit activity that spreads to other muscles remote to the site of stimulation – corresponds to spasms
• Pathology
• thought to be due to decreased descending control of spinal cord reflexes
• Possible increase monoaminergic descending excitation or decrease GABA inhibition
• Investigation:
• Anti-GAD (glutamic acid decarboxylase) Abs present in 60-80%, serum non-specific; therefore get CSF to confirm intrathecal AB production; Abs to pancreatic islet cells (50-60%), gastric parietal cell Abs (50%), Thyroid microsomes (30-40%)
• CSF – Oligoclonal bands in 60%, occasionally pleocytosis
• DDx:
• Dystonia – improves supine and rest, and related to movement, reflexes unchanged,
• Myotonia / neuromyotonia – distal muscles, delayed relaxation, EMG characteristic
• Myopathies of spine – rigid spine syndrome
• Segmental spasms/rigidity – MS, TM, tumors of brainstem and spinal cord, AVMs
• Psychogenic – MOST common initial diagnosis
• Variants
• Progressive encephalomyelitis with rigidity and myoclonus – associated oculomotor disturbances, ataxia, vertigo, brainstem myoclonus – more rapid course
• Stiff Limb Syndrome – autoimmune begins in leg – Paraneoplastic begins in ARM
• Paraneoplastic encephalomyelitis and SMS – amphiphysin Abs – Breast and SCLC – rapid progression - otherwise identical to typical SMS
• Rx –
• IV Dazepam can be used almost diagnostically as it rapidly improves rigidity / stiffness
• Oral Diazepam (1st line) – up to 100mg / day as disease progresses
• 2nd line – Oral baclofen, tizanidine, IVIg, steroids, IV methylprednisolone
Painful Legs-Moving Toes
• Onset of varied intensity pain followed by complex patterned toe movements that are involuntary, may be aborted or precipitated by foot movement – usually secondary to known lesion including spinal cord, root or nerve damage – Mx – very difficult, none known to be successful
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