Movement disorders Notes

NOTES NOTES MOVEMENT DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders causing abnormal movement ▫ Increased voluntary/involuntary movement (hyperkinetic disorders); reduced movement (hypokinetic disorders) TYPES Acute fulminant episodes ▪ Reaction to trigger, medication (neuroleptic malignant syndrome) Benign chronic conditions ▪ Restless legs syndrome (RLS), essential tremor Progressive chronic syndromes ▪ Parkinson’s disease (PD), Friedreich’s ataxia CAUSES ▪ Often idiopathic; genetic mutations, medication SIGNS & SYMPTOMS ▪ Mild, unpleasant sensations, intention/ action tremors; rigidity, catatonia 638 OSMOSIS.ORG ▪ Motor abnormality ▫ Hypokinesia: ↓ amplitude ▫ Bradykinesia: ↓ speed ▫ Dyskinesia: unwanted, characterized motor movement ▫ Tremor: rhythmic motor movement; resting, action, postural ▫ Rigidity: abnormal, uncoordinated muscle tone across joint DIAGNOSIS OTHER DIAGNOSTICS ▪ Neurologic examination ▫ Observation of spontaneous movement, strength testing, tone evaluation, reflex exam TREATMENT MEDICATIONS ▪ Beta blockers, anti-epileptics, benzodiazepines; dopamine replacement, agonists OTHER INTERVENTIONS ▪ Avoid caffeine, nicotine, etc. ▪ Educational, supportive therapy

Chapter 83 Movement Disorders ESSENTIAL TREMOR osms.it/essential-tremor PATHOLOGY & CAUSES ▪ Most common movement disorder; involuntary, rhythmic shaking ▪ Usually affects hands, fingers; sometimes head, vocal cords ▪ Action tremor (occurs during muscle effort) ▫ Postural/intention tremor CAUSES ▪ Unknown; may be familial with autosomal dominant inheritance pattern RISK FACTORS ▪ Meat consumption ▫ Exposure to heterocyclic amines (e.g. harmane, harmaline) ▪ Associated with dystonia (cervical, spasmodic, cranial dystonia, writer's cramp), parkinsonism SIGNS & SYMPTOMS ▪ Rhythmic, symmetrical tremor ▫ Hands, head, vocal cords, neck, face, leg, tongue, trunk ▪ High frequency tremor (4–12Hz) exacerbated by muscle contraction ▪ Inability to perform precise tasks ▪ Intention tremor ▫ Intensifies upon touching nose with finger ▪ Postural tremor ▫ During outstretched arms ▪ Walking difficulties ▪ ↓ tremor with alcohol intake DIAGNOSIS OTHER DIAGNOSTICS ▪ Postural/action tremor of hands/head; duration ≥ three year ▪ Alleviation with alcohol intake Physical examination ▪ Fine postural, action tremor in hands, head/ voice ▪ Asymmetric/symmetric: cogwheel rigidity, resting tremor, dystonia (esp. head) TREATMENT MEDICATIONS ▪ If disabling, symptomatic treatment ▫ Beta blockers ▫ Anti-epileptics ▫ Benzodiazepines ▫ Botulinum toxin (head tremors not responsive to medication) OTHER INTERVENTONS ▪ Avoid caffeine, nicotine, etc. ▪ Get enough sleep OSMOSIS.ORG 639

FRIEDREICH'S ATAXIA osms.it/friedreichs-ataxia PATHOLOGY & CAUSES ▪ Genetic disorder; causes progressive central nervous system (CNS) damage, movement problems ▪ Predominantly affects CNS; also affects heart, pancreas ▪ ↓ frataxin → ↓ mitochondrial oxidative phosphorylation → cell damage, death ▪ ↓ frataxin → ↑ free iron → ↑ oxidative stress → cell damage, death ▪ Neuronal cell death affects posterior columns of spinal cord, distal corticospinal tracts, spinocerebellar tracts, brain stem, cerebellum ▪ Gene silencing → no frataxin synthesized → iron accumulates in cell, reacts with oxygen → unstable oxygen radicals → cell death CAUSES ▪ Trinucleotide repeat GAA expansion (chromosome 9q13) → ↓ production of mitochondrial inner membrane protein, frataxin ▫ Autosomal recessive inheritance pattern ▫ ↑ repeats → ↑ severity, ↓ age of onset 640 OSMOSIS.ORG ▫ 600–1200 trinucleotide repeats → Friedreich’s ataxia COMPLICATIONS Progressive loss of cells ▪ In CNS, heart, pancreas ▪ Limb, gait ataxia → wheelchair bound → bedridden ▪ Dysphagia, dysarthria → aspiration → gastric bacteria insult to respiratory parenchyma ▪ Hypertrophic cardiomyopathy (secondary to myocardial cell death) ▫ Fibrosis → arrhythmia, hypertrophic cardiomyopathy → heart failure ▫ Most common cause of death in affected individuals (age 40–50) ▪ Diabetes mellitus ▫ Loss of beta cells of pancreas ▪ 25% of affected individuals ▪ Musculoskeletal abnormalities ▫ Muscle denervation → abnormal forces about joints → abnormalities ▪ Kyphoscoliosis ▫ Severe → ↓ total lung capacity → restrictive lung disease

Chapter 83 Movement Disorders ▪ Pes cavus ▫ Similar restrictive lung disease in severe cases ▪ Hammer toes SIGNS & SYMPTOMS ▪ Ataxia ▫ Falling/staggering while walking, widebased gait ▫ Gait ataxia most common (age 0–10); most individuals progress to wheelchair dependence within 11–25 years ▪ Loss of vibratory sense, proprioception ▪ Muscle weakness, chest pain, dyspnea, heart palpitations, absence of tendon reflexes in legs, involuntary eye movements, action tremor, hand clumsiness, dysarthria, fatigue DIAGNOSIS LAB RESULTS Genetic testing ▪ Confirms diagnosis ▪ GAA repeats; examine first intron in frataxin gene OTHER DIAGNOSTICS ▪ Symptom progression, family history ▪ Neurological exam ▫ Ataxia (gait, hand); ↓ vibratory sensation, proprioception; ↓ deep tendon reflexes, nystagmus Electromyogram ▪ Absent/reduced sensory nerve action potentials ▪ Normal/only slightly decreased motor nerve conduction velocities ▪ Abnormal auditory, visual, somatosensoryevoked responses TREATMENT OTHER INTERVENTIONS ▪ Occupational, physical therapy ▫ Balance, ataxic progression ▪ Cardiology ▫ Annual electrocardiogram, echocardiogram ▪ Severe scoliosis ▫ Orthopedic referral ▪ Annual diabetes screening ▪ Genetic, psychological counseling services OSMOSIS.ORG 641

NEUROLEPTIC MALIGNANT SYNDROME osms.it/neuroleptic-malignant-syndrome PATHOLOGY & CAUSES ▪ Life-threatening idiosyncratic reaction to antipsychotic drugs; muscle rigidity, fever, altered mental status, autonomic dysfunction ▪ Dopamine blockade theory ▫ Central dopamine blockade → hypothalamus → hyperthermia, dysautonomia ▫ Nigrostriatal dopamine blockade → tremor, rigidity ▪ Peripheral muscle theory ▫ Direct toxic effect of neuroleptics → mitochondria of skeletal muscle → rigidity, fever ▪ Sympathetic nervous system theory ▫ ↓ dopamine inhibitors → ↑ sympathetic output ▫ ↑ sudomotor, vasomotor activity → fever CAUSES Reaction to medications ▪ First-generation neuroleptic (most common) ▫ Haloperidol, fluphenazine, chlorpromazine ▪ Second-generation neuroleptic medication ▫ Clozapine, risperidone, olanzapine ▪ Antiemetic ▫ Metoclopramide, promethazine, droperidol ▪ Withdrawal of L-Dopa/dopamine agonist therapy (Parkinson disease) RISK FACTORS ▪ Increase in dose/change of neuroleptic medication ▪ Abrupt cessation/reduction of dopaminergic medication 642 OSMOSIS.ORG ▪ Lithium/alcohol/psychoactive substance use ▪ Previous episode of neuroleptic malignant syndrome ▪ Acute injury (e.g. trauma, surgery, infection) ▪ Psychiatric conditions (e.g. acute catatonia, severe agitation) ▪ Lewy body dementia COMPLICATIONS ▪ Rhabdomyolysis, renal failure ▪ Seizures ▫ Due to hyperthermia, metabolic imbalances ▪ Encephalopathy, stupor, coma ▪ Cardiac arrhythmias (e.g. torsades de pointes, cardiac arrest) ▪ Disseminated intravascular coagulation SIGNS & SYMPTOMS Altered mental status ▪ Agitated delirium with confusion (initial symptom); coma Muscular abnormalities ▪ Generalized muscular rigidity (“lead-pipe rigidity”) ▫ Associated dysphonia, dysarthria ▪ Catatonic signs ▪ Extrapyramidal symptoms ▫ Tremor, chorea, akinesia ▪ Less common ▫ Dystonic movements (e.g. opisthotonos, trismus, blepharospasm), mutism, dysarthria, dysphagia Hyperthermia ▪ Temperatures > 38–40°C/100.4–104°F

Chapter 83 Movement Disorders Autonomic dysfunction ▪ Tachycardia, labile/elevated blood pressure, tachypnea, sialorrhea, profuse diaphoresis (sweating), flushing, incontinence DIAGNOSIS LAB RESULTS ▪ Severe ↑ creatine kinase (CK) ▫ Correlates with rigidity severity → 1–100k international units/L ▪ Mild ↑ lactate dehydrogenase, alkaline phosphatase, liver transaminases ▪ Electrolyte imbalances ▫ ↓ Ca2+, ↓ Mg2+, ↓ Na+/↑ Na+, ↑ K+, metabolic acidosis ▪ ↑ white blood cell count (leukocytosis) 10–40k ▪ Myoglobinuria ▪ ↓ serum iron concentration OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Altered mental status → hyperthermia, rigidity → autonomic dysfunction TREATMENT MEDICATIONS ▪ Discontinue offending neuroleptic agent ▪ Dantrolene (skeletal muscle relaxant), bromocriptine (dopamine agonist); both (if severe) to reduce muscle rigidity, hyperthermia OTHER INTERVENTIONS ▪ Maintain cardiorespiratory stability ▫ Intubation, mechanical ventilation ▪ Temperature reduction ▫ Cooling blankets, ice water gastric lavage, ice packs in axilla; acetaminophen/aspirin ▪ Correct fluid, electrolyte imbalance ▫ ↓ CK damage/accumulation; replete insensible losses from diaphoresis ▫ Benzodiazepines: ↓ uncontrollable agitations ▪ Electroconvulsive therapy ▫ If not responsive to medical therapy in first week; if severe/lethal catatonia OSMOSIS.ORG 643

PARKINSON'S DISEASE osms.it/parkinsons-disease PATHOLOGY & CAUSES ▪ Degeneration of dopaminergic neurons in substantia nigra → tremor, rigidity, akinesia, postural instability ▪ Most common neurological disorder; onset after age 50 ▪ Degeneration of neurons in substantia nigra → dopamine depletion from basal ganglia → disruption of connection to thalamus, motor cortex → Parkinsonism ▪ Exact mechanism unknown; build-up of abnormal proteins into Lewy bodies in neurons; accompanied by death of astrocytes, significant increase in microglia of substantia nigra ▪ Protein (e.g. alpha-synuclein) accumulation in neuron → abnormal intracellular transit → neuronal damage, death → motor symptoms ▫ Asymptomatic neuronal degeneration: brainstem (locus coeruleus) ▫ Symptomatic neuronal degeneration: basal ganglia; dopaminergic substantia nigra pars compacta neurons diseased, die → dennervate striatum → dysfunctional basal ganglia → hypo/ bradykinetic motor output ▫ Late degeneration: cerebral cortex; leads to cognitive impairment CAUSES ▪ Usually idiopathic ▪ Mutation of PINK1, parkin, alpha synuclein genes ▪ Toxicity in recreational drug MPPP (synthetic opioid); rare RISK FACTORS ▪ Family history, previous head injuries, pesticides exposure ▪ Protective factors ▫ Caffeine, nicotine 644 OSMOSIS.ORG COMPLICATIONS ▪ Freezing phenomenon ▫ Progressive hypokinesia, bradykinesia → (akinetic) pauses in movement; common when walking; tend to occur at thresholds (e.g. door frames) ▪ Falls ▫ Secondary to postural instability, poor movement amplitude ▪ Dystonia ▫ Abnormal tone across joints → disfiguring, painful posturing; universal flexion of joints → severely kyphotic posturing → poor ability to ambulate, ventilate ▪ Dementia ▫ Common after prolonged, primarily motor disease (in contrast to Lewy body dementia); psychosis, hallucinations (severe) SIGNS & SYMPTOMS ▪ Psychiatric ▫ Depression, anxiety, mood disturbances; impairment of cognitive function, dementia (advanced stages) ▪ Sleep disturbances ▫ Wild dreams ▪ Autonomic dysfunction ▫ Orthostatic hypotension, constipation, increased sweating ▪ ↓ olfactory sense ▫ Common first symptom; history of ↓ / changed sense of taste, smell prior to motor symptoms ▪ Micrographia

Chapter 83 Movement Disorders MNEMONIC: TRAPS Parkinson’s disease symptoms Tremor (resting tremor) Rigidity Akinesia Postural changes (stooped) Stare (serpentine stare) DIAGNOSIS OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Resting tremor, rigidity, bradykinesia ▫ Dopaminergic medication response ▪ Postmortem autopsy ▫ Loss of pigmented dopaminergic neurons of substantia nigra pars compacta ▫ Lewy bodies (intracytoplasmic eosinophilic inclusions), neurites TREATMENT MEDICATIONS ▪ Symptomatic treatment; see mnemonic MNEMONIC: SALAD Common Parkinsonism treatments Selegiline Anticholinergics: trihexyphenidyl, benzhexol, orphenadrine L-Dopa + peripheral decarboxylase inhibitor: carbidopa, benserazide Amantadine Dopamine postsynaptic receptor agonists: bromocriptine, lisuride, pergolide Dopamine replacement ▪ Precursor to dopamine → ↑ dopamine synthesis → ↑ synaptic dopamine → ↓ motor symptoms ▪ Commonly formulated with carbidopa (peripheral decarboxylase inhibitor) ▫ Carbidopa-mediated inhibition of liver, systemic carboxylation → levodopa cross blood brain barrier (BBB) → ↑ dopamine formation ▪ Adverse effects ▫ On/off phenomena: return of symptoms prior to next dose; due to half life of levodopa (approx. 90 minutes) ▫ Dyskinesia, dystonia: abnormal, repetitive movement (dyskinesia), abnormal sustained muscle contraction (dystonia); head, neck (e.g. tardive dyskinesia of tongue, cervical torticollis); ↑ incidence with ↑ dosing, duration of disease ▫ Neuroleptic malignant syndrome: when discontinued abruptly/high, multiple doses missed Dopamine agonists ▪ ↑ dopaminergic stimulation of postsynaptic receptors → ↓ motor symptoms ▪ Adverse effects ▫ Dyskinesia ▫ Impulse control disorder: ↑ risk-taking behavior (e.g. pathologic gambling; compulsive sexual behavior, shopping) OSMOSIS.ORG 645

Monoamine oxidase B (MAO-B) inhibitors ▪ ↓ MAO-B-related dopamine metabolism → ↑ synaptic dopamine → ↓ motor symptoms ▪ Most effective for mild-moderate symptoms Anticholinergic ▪ Improves neurochemical imbalance in basal ganglia ▪ Most useful in young (< 70) individuals with tremor as primary symptom; less useful for rigidity, bradykinesia ▪ Anticholinergic side effects common Amantadine ▪ Antiviral drug ▫ Known NMDA receptor agonist; ↓ neurotransmitter imbalance i ▪ Most useful in mild disease SURGERY ▪ Deep brain stimulation (DBS) ▫ Direct neural stimulation of basal ganglia (either subthalamic nucleus of globus pallidus interna) → ↑ motor output of basal ganglia → ↓ motor symptoms ▫ Severe/medication nonresponsive disease OTHER INTERVENTIONS ▪ Education, support ▫ Physical, emotional aspect of degenerative, debilitating disease ▪ Physical therapy ▫ Exercise → ↓ incidence of falls Catechol-O-methyltransferase (COMT) inhibitors ▪ ↓ dopamine, levodopa metabolism → ↑ synaptic dopamine → ↓ motor symptoms ▪ Rarely used as monotherapy RESTLESS LEG SYNDROME osms.it/restless-legs-syndrome PATHOLOGY & CAUSES ▪ Uncontrollable urge to move legs, relieved by movement ▪ Affects legs, feet bilaterally; less commonly affects arms CAUSES ▪ Unknown ▪ CNS ▫ ↓ iron, dopamine ▪ Peripheral nervous system ▫ Abnormal A fibers, peripheral nerve microvasculature 646 OSMOSIS.ORG TYPES Primary RLS ▪ Idiopathic; runs in families; onset < 45 years old; progressive, worsens over time Secondary RLS ▪ Associated with underlying medical conditions, medications; onset > 45 years RISK FACTORS ▪ Pregnancy, iron deficiency/anemia, smoking, caffeine, Parkinson’s disease, family history, renal failure, obesity ▪ Peripheral neuropathy (due to diabetes, alcoholism, rheumatoid arthritis, etc.)

Chapter 83 Movement Disorders ▪ Medications ▫ Antidepressants, antiemetics, antipsychotics, antihistamines, calcium channel blockers ▪ More common in individuals who are biologically female COMPLICATIONS ▪ Insomnia → daytime drowsiness SIGNS & SYMPTOMS ▪ Strong urge to move legs while resting; unpleasant sensations (e.g. tingling, burning, crawling, itching, aching) ▪ Relief by movement; worsening of symptoms in evening/night → insomnia ▪ Nighttime leg twitching while asleep Aggravating factors ▪ Antihistamines ▫ Commonly used for sleep assistance ▪ Dopamine antagonists ▪ Psychiatric medications ▫ Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) TREATMENT MEDICATIONS ▪ If other interventions not effective ▪ Dopamine agonists (e.g. pramipexole, ropinirole) ▪ Alpha-2-delta calcium channel ligands (e.g. pregabalin, gabapentin) ▪ Benzodiazepine ▫ Individuals with intermittent symptoms ▪ Iron replacement ▫ ↓ symptom severity when low (< 75ng/ ml) serum iron levels repleted OTHER INTERVENTIONS ▪ Lifestyle changes ▫ Avoid aggravating factors/situations, ↓ caffeine intake ▪ Mental alert activities ▫ Distract individual in times of symptoms DIAGNOSIS OTHER DIAGNOSTICS Clinical Presentation ▪ Urge to move limbs with/without unpleasant sensations ▪ Improvement with activity ▪ Worsening at rest/in evening OSMOSIS.ORG 647