Neurology - PRITE

Clinical Neurology for Psychiatrists Chapter 6
Muscle Disorders PRITE study guide

Muscle Disorders
•Muscle disorders can be divided into those of the NMJ and disorders of the muscles themselves (myopathies)
•May be associated with mental retardation, cognitive decline, personality changes, need for psychotropic medications

NMJ Disorders
•Myasthenia gravis – (see handout emailed out by Helen Farrell)
–Neuromuscular transmission impairment
–ACh receptor antibodies block, impair, destroy the ACh receptors
–Selectively attack those in the extraocular, facial, neck, proximal limb muscles
–Affected receptors produce only weak, unsustained muscle contractions
–Attack only nicotinic ACh receptors
–Antibodies do not penetrate blood brain barrier, do not intefere with CNS function
–Readily passes thru placenta so may cause transient myasthenia graves in the neonate
–Some people have antibodies called MuSK (antimuscle specific kinase) instead of to ACH

Myasthenia Gravis
•Standard medicines either increase ACh concentration at the NMJ or restore the integrity of ACh receptors
•First line tx: anticholinesterases, cholinergic inhibitors
–Edrophonium (tensilon)
–Pyridostigmine (mestinon)
–These medicines inactivate cholinesterases and prevents them from chewing up ACh
–Prolonging ACh activity increases strength

Other Meds
•Steroids and immunosuppressants
•Plasmapheresis
•IVIG

Botulinum Toxin
•Blocks release of ACh packets from the presynaptic membrane and causes paresis

Succinylcholine
•Binds ACh receptors at postsynaptic side of neuromuscular junction
•When the receptors are inactivated, muscles weaken to the point of flaccid paralysis
•Resists cholinesterases so it paralyzes for hours
•Used in surgery and ECT

ACh
•Serves as a transmitter at NMJ and in CNS
•Its action is terminated mostly by metabolism instead of reuptake
•Antibodies associated with myasthenia gravis affect the NMJ but not the CNS because NMJ has nicotinic ACh receptors and CNS has muscarinic ACh receptors

Pyridostigmine
•Anti-acetylcholinesterase medication that unlike most in its class does cross the blood brain barrier
•Preserves acetylcholine in the CNS
•Helpful theoretically for Alzheimer’s because that disease has low CNS ACh levels
–In practice however studies show no benefit despite actually increasing ACh levels

Clinical Features of MG
•Fluctuating, asymmetric weakness of the extraocular, facial and bulbar muscles
•Repetitive activities weaken the muscles
•Symptoms appear in the PM
•Rest alleviates symptoms
•Usually affecting young women or other men
•Develop diplopia or ptosis as first symptom
•Tend to grimace when trying to smile, nasal speech

Clinical Features of MG 2
•Advanced disease -> neck, shoulder, swallowing, respiratory muscles become weak
•Leads to bulbar palsy
•Severe cases -> resp. distress, quadriplegia, inability to speak (anarthria), may reach a “locked-in state” with severe paralysis
•Cognition not affected, visual acuity not affected, pupillary rxn intact, bladder and bowel f(x) intact, sensation intact

MG and Pregnancy
•40% pregnant women have a flare up
–Occurs with equal frequency in each trimester
•30% pregnant women have remission from MG while pregnant

Clinical Dx of MG
•Positive tensilon test
•Detection of serum ACh receptor antibodies
•EMG results indicating MG
•Check also for: hyperthyroidism (5%) or mediastinal thymoma (10%) – which if treated improves the MG

DDx
•Lesions of oculomotor nerve
–Caused by Midbrain infarction
–Also caused by compression of posterior communicating artery aneurysms
–Result in extraocular muscle paresis
–Abrupt and painful onset
–Pupil is widely dilated and unreactive to light because of intraocular (pupillary) muscle paresis

Diseases that Cause Facial and Bulbar Palsy
•ALS
•Guillain Barre
•Lyme disease
•Lambert Eaton syndrome
•Botulism

•Only Myasthenia gravis responds to the tensilon test consistently

Lambert Eaton Syndrome
•Impaired ACh NMJ transmission -> weakness
•Affects the presynaptic release of ACh instead of the postsynaptic release of ACh like in MG
–Botulism is similar but it is a toxin
–Because these are antibodies it is called Lambert-Eaton
•Antibodies are directed vs presynaptic voltage gated calcium channels

Lambert Eaton vs. MG
•Lambert Eaton associated with small cell CA (paraneoplastic)
•Less common than MG
•Lambert Eaton causes weakness of the limbs
•Repetitive exertion temporarily makes weakness better
•Lambert Eaton causes autonomic sys dsyfunction

Lambert Eaton vs. Botulism
•Botulism is caused by a eating contaminated food
•Botulism causes oculomotor, bulbar, respiratory paralysis that resemble Guillan Barre and MG
•Botulism symptoms arise explosively with dilated unreactive pupils, n/v, diarrhea, fever
•Many family members who ate the food may be affected at the same time 18-36 hours later
•Clostridium botulinum

Botulinum toxin as Rx
•Helps with
–Writer’s cramp
–Spasmodic torticollis
–Blepharospasm
–Other focal dsytonias and dyskinesias

Tetanus
•Clostridium tetani
•Blocks presynaptic release of CNS inhibitory neurotransmitters GABA and glycine
•Causes increased muscle contractions like:
–Trismus, facial grimacing, risus sardonicus
•Affects drug addicts, workers in farming and scrap metal recovery, hx in illegal abortions

DDx for Acute Contractions
•Spasmodic contractions of the face or jaw can be caused by:
–Neuroleptic induced dsytonic reaction
–Heat stroke
–Strychnine poisoning
–Rabies

Organophosphate Exposure
•Bind and inactivate AChE
•AChE accumulates and irreversibly depolarizes postsynaptic NMJs
•Cause respiratory muscle paralysis
•Malathion – pesticides, hx of suicide attempts in India with organophosphates
•Nerve gases – sarin

Organophosphate Exposure 2
•Accumulation of AChE causes cholinergic crisis
•Tearing, pulmonary secretions, miosis
•Causes convulsion, resp depression
•Pretreatment with pyridostigmine – AChE inhibitor
•Wash skin with dilute bleach
•Post exposure give oximes to detox because they are competitive inhibitors of ACh, block anticholinergic activity
•Watch for seizure, give BZD only as other AEDs ineffective

Nerve Gas Exposure
•HA
•Personality changes
•PTSD
•Cognitive impairment
–Memory

Agent Orange
•Herbicide sprayed on Vietnam during war
•Caused peripheral neuropathy, cognitive impairment, psychiatric illness, brain tumors
•Science has not found evidence for Agent Orange actually causing these problems

Persian Gulf War Syndrome
•Fatigue, weakness, myalgias
•No evidence of neurologic disorder despite symptoms in soldiers

Chronic Fatigue/Fibromyalgia
•Chronic fatigue
–Symptoms vary widely
–Labs, EMG reveal no findings

•Fatigue is characteristic with cognitive impairment in these diseases:
–Lyme dz, AIDS, mononucleosis, MS, OSA
–Deconditioning

Chronic Fatigue/Fibromyalgia 2
•Subjective symptoms of chronic widespread pain, diffuse tenderness (formerly thought to be tender points)
•No objective findings (labs, tests) support the symptoms
•Associated with depression, irritable bowel syndrome, atypical chest pain, transformed migraine

Muscle Disease (Myopathy)
•Affect shoulder and hip girdle muscles
•Proximal muscles affected first and most severely
•Problems climbing stairs and combing hair
•Ok with strength in oculomotor, sphincter, (hands and feet muscles Ok b/c they are distal, more affected by neuropathies usu.)
•Acute inflammatory myopathies -> myalgias, tenderness

Myopathies
•Result in muscle weakness and dsytrophy (atrophy of muscle fibers)
•DTRs usually normal or hypoactive
•No Babinski signs or sensory loss because corticospinal and sensory tracts not affected
•Creatine phosphokinase (CK) and aldolase are elevated and EMGs are abnormal
•Usually do not cause concomitant psychiatric disease

Duchenne Muscular Dystrophy
•Most frequently occuring childhood onset myopathy
•Sex linked trait -> affecting boys usually, sometimes female carriers as well
•Chronic, progressively incapacitating course, fatal
•Affects thighs and shoulders
•Muscles that are the weak look bigger because connective tissue and fat accumulate there – pseudohypertrophy
•Gower’s sign – way of getting up from floor despite deficits in muscles
•Wheelchair bound by 12 yo

DMD
•PMR is often present
•IQ is 1 standard deviation below normal
•Intellectual impairment does not progress
•No cure
•Transplant of muscle cells, gene transfer promising possible treatment

DMD Genetics
•DMD results from absence of dsytrophin
•Defective gene is on the short arm of the x chromosome
•Genetic testing is available
•Result of DNA deletion whereas other dystrophies are because of a trinucleotide repeat (myotonic dsytrophy)
•May diagnose based on muscle biopsy as well

Becker's Dystrophy
•More benign variant of DMD
•Different mutation in dsytrophin gene
•Causes symptoms of weakness that begins in 2nd decade and follows a slowly progressive course
•No cognitive impairment

Myotonic Dystrophy
•Most common dystrophy in adults
•Appears at 20-25 yo, M=F
•Facial and limb weakness
•Myotonia is characteristic = involuntary prolonged muscle contraction, difficulty releasing grip after handshake for ex.
•Tap the thumb with a reflex hammer and watch it make a prolonged medial movement or make a fist and release

Myotonic Dystrophy 2
•Facial muscle atrophy – “hatchet face”
•Balding over temples, sunked and elongated face, ptosis, prominent forehead
•Also causes: cataracts, cardiac conduction, system disturbances, endocrine organ failure
•TX: comorbid conditions, myotonia treated with phenytoin quinine
•Have limited IQ and progressive cognitive deficits with age
•Personality with blandness and lack of initiative High incidence of avoidant personality disorder

Myotonic Dystrophy 3
•Trinucleotide repeat
•Genetic anticipation – greater numbers of repeats in offspring cause greater symptoms and earlier age of onset

Myotonic Dystrophy 4
•Channelopathies
•CTG trinucleotide repeat
•Autosomal dominant
•On chromosome 19Causes abnormal ion channels in the membranes of muscle and other organ cells

Diseases with Trinucleotide Repeats
•Freidrich’s ataxia - autosomal recessive pattern
•Spinocerebellar atrophy, Huntington’s disease – autosomal dominant
•Fragile x syndrome – sex-linked pattern
•Diagnosed by testing wbc DNA
•Severity of the disease proportional to the length of the repeats

Trinucleotide Repeats
•Sperm are more likely than eggs to increase their DNA repeats
•Fathers more likely than mothers to pass on more severe form of illness
•Amplification – trinucleotide repeats are unstable and can expand when transmitted to child
•Ascertainment bias- apparent increase in incidence resulting from closer scutiny (epidemiologic error)

Polymyositis
•Nonspecific, generalized, inflammatory myopathy characterized by weakness, myalgias, and constitutional signs
•When accompanied by rash on face, extensor surfaces of elbows and knees – dermatomyositis
•May be associated with polymyalgia rheumatica, polyarteritis nodosa

Trichinosis
•Infectious myopathy
•Thru eating undercooked pork or wild game
•Often found in recent Hispanic immigrants
•Develop characteristic muscle pain, fever, heliotrope rash

Eosinophilia-Myalgia Syndrome
•Tryptophan toxicity – supplements taken by insomniacs or health food devotees
•Several days of severe myalgias, high level of eosinophils in blood
•Also with fatigue, rash, neuropathy, cardiopulmonary impairments
•Danger of being mislabeled as having chronic fatigue snydrome Often pts have delpression as well

AIDS Myopathy
•Myalgia, weakness, weight loss, fatigue
•Likely cause is AZT
•Muscle biopsies show abnormalities in mitochondria
•Withdrawing the offending medicine partially improves this

Metabolic Myopathies
•Myopathies that cause muscle and cerebral impairments
•Prolonged steroid treatment – produces proximal muscle weakness, wasting
–Cushingoid appearance
–Steroid psychosis
–Most likelt to occur in patients with brain tumors, cereberal vasculitis
–Anabolic steroid users are prone to steroid psychosis and steroid myopathy

HYPO-K Myopathy
•Low serum K concentration leads to muscle weakness
•Cardiac arrhythmias
•Usually iatrogenic and caused by administration of diuretics and steroids
•Sometimes this is a factitious disorder
•Sometimes occurs with laxative abuse and cirrhosis d/t etoh

HYPO-Na Myopathy
•Low sodium causes confusion, agitation, stupor, seizures
•Other causes
–Compulsive polydipsia
–Use of tegretol, trileptal, lithium, ssris

HYPO-K Periodic Paralysis
•Involves potassium metabolism
•Attacks lasting hours to 2d of areflexic quadriparesis
•Pts remain alert, fully cognizant, breathing normally, purposefully moving eyes
•Happens irregularly
•Exercise, sleep, large carb meal precipitates them
•Like sleep paralysis, cataplexy – but usually for longer duration
•Autosomal dominant, usu in teen boys
•Mutation in calcium ion channel gene – channelopathy
•Occurs with hyperthyroidism in adults

Myopathies Causing MS Change
•Alcoholism – limb and cardiac muscle wasting
•Hyperthyroid myopathy – weakness
•Apathetic hyperthyroidism – signs of overactivity are not present
•Metabolic myopathies resolve when normal metabolism is restored

Myopathies Causing Elevated CK
•Clozapine – elevated CK, but rarely a clinically detectable myopathy
•Statins – may cause muscle inflammation ranging to rhabdomyolysis

Mitochondrial Myopathies
•Mitochondria remove free radicals
•MtDNA derived from mother only, ds ringshaped with only 37 genes
•Abnormal mtDNA is mixed with normal in amounts that are random
•If the abnl mtDNA reaches threshold then the mitochrondria will not be able to produce ATP
This is called heteroplasty and it is the reason why the severity of mt diseases are variable

Mitochondrial Myopathies 2
•Abnormalities in cellular DNA can cause mt DNA problems
•Causes Wilson’s disease, Friedrich’s ataxia
•A father might transmit a mitochrondrial disease to a child because his cellular DNA are abnormal and cause the mtDNA to malfunction

Mitochondrial Myopathies 3
•Impaired muscle metabolism
•Brain damage
•Abnormal lipid storage
•Affected muscle fibers appear as ragged red fibers
•Cytochrome c oxidase COX is absent and other normal respiratory enxymes not there as well

Mitochondrial Myopathies 4
•Primarily mitochondrial myopathies – result from mt having deficiencies in cytochrome oxidase
•Causes weakness, exercise intolerance, short stature, epilepsy, deafness, episodes of lactic acidosis
•Progressive opthalmoplegia – cause ptosis, extraocular muscle palsies, retinitis pigmentosa, short stature, cardiomyopathy, endocrine abnormalities

Mitochondrial Myopathies 5
•Leber’s optic atrophy – hereditary optic atrophy in young men
•Mitochondrial encephalopathies – progressively severe or intermittent mental status abnormalities that usually appear between infancy and 12 yrs
•Children have MR, progressive cognitive impairment, episodes of confusion leading to stupor
•May also cause paresis of the extraocular muscles, PMR, regression, migraine like HA, optic atrophy

Mitochondrial Encephalopathies
•Progressively severe or intermittent mental status abnormalities
•Appear between infancy and 12 years
•May include: mental retardation, progressive cognitive impairment or episodes of confusion leading to stupor
•May also cause: paresis of extraocular muscles, PMR, migraine like HA, optic atrophy

Mitochondrial Encephalopathies 2
•Mt Respiration malfunction - Leads to lactic acidosis constantly or only during attacks
•Muscle biopsies -> ragged red fibers that have large amts of mt and a checkerboard pattern of cells that fail to stain for cytochrome c oxidase
•MELAS – mitochondrial encephalopathy, lactic acidosis, stroke like episodes
•MERRF – myoclonic epilepsy, ragged red fibers

Neuroleptic Malignant Syndrome
•Intense muscle rigidity, fever, autonomic dsyfunction
•Other names: Parkinson-hyperpyrexia, central dopaminergic syndrome
•Rigidity causing muscles to crush themselves (muscle necrosis)
•Crushed muscles release myoglobin -> myoglobinemia, myglobinuria
•Myoglobin can precipitate in the renal tubules and cause renal dsyfunction

NMS 2
•Rhabdomyolysis – elevated CK
•Renal impairment raises BUN, creatinine concentrations
•EEG with diffuse slowing – mild abnormality indicative of a toxic or metabolic cause
•Causes tachycardia or CV collapse
•Intense generalized muscle contractions, elevated temperatures, may cause cerebral cortex damage

NMS 3
•Usually in agitated, dehydrated men who have received neuroleptics in large doses over a brief period
•Meds that cause it: typicals, atypicals, dopamine blocking agents, withdrawal of L-dopa, PCP intoxication
•Possible causes: sudden dopamine deficiency, dopamine-blocking psychotropics alter the calcium distribution in the cells

NMS Rx
•L-dopa and bromocriptine – restores dopamine-like activity
•Apomorphine can be injected which is an injectable dopamine agonist (causes n/v)
•Dantrolene – restores intracellular calcium
•ECT? – unclear if this really helps

Serotonin Syndrome
•Iatrogenic
•Muscle hypertonicity
•Symptoms: tremulousness, myoclonus, clonus, agitated confusion
•Signs of autonomic instability: mydriasis, diarrhea, tachycardia, hypertension, fever
•Excessive CNS and PNS serotonin stimulation
•Meds that cause it: serotonin precursors, ssri, TCA, amphetamine, MAOIs, sumatriptan, St. Johns’s wort

Serotonin Syndrome 2
•Watch for use of MAOI Deprenyl in Parkinson’s disease
•Neurologist diseases often are treated by serotonergic agents and pts become depressed so they are given serotonergic antidepressants
•Causes myoclonus, usually no fever, CK elevation
•Remove offending agent, then support vital functions, decrease muscle rigidity, reduce agitation
•Treat with cyproheptadine
•2nd line – chlorpromazine (serotonin antagonist), ECT

Malignant Hyperthermia
•Leads to rhabdomyolysis, hyperthermia, brain damage, death
•Caused by general anesthesia or succinylcholine
•Excessive calcium release by calcium channel
•Inherited diathesis: autosomal disorder on chromosome 19
•Review family history before surgery
•Dantrolene – treatment

Sx: AMS + Hyperthermia + muscle abnormalities

Diseases that might cause these are:
•Meningitis
•PCP
•Heat stroke
•Delirium tremens

Anticholinergic Poisoning
•In the DDX for fever and agitated delirium
•May also cause excessive sympathetic activity (mydriasis, dry skin, urinary retention, absent bowel sounds)
•Check to see if patient has muscular hypertonicity, or bladder or bowel hyperactivity – if so, then it is not anticholinergic poisoning

Nerve Conduction Velocity Studies
•Determine the site of nerve damage
•Confirm clinical diagnosis of polyneuropathy from myopathy
•Separate neuropathies that have resulted from loss of myelin – different NCVs
•Normal NCV is 50-70 m/sec
•Nerve damage may be focal or diffuse (DM)
•Myopathies do not slow NCVs

Electromyography
•Inserting needles into muscles, looking at complete muscle rest, voluntary contractions, stimulation of the innervating peripheral nerve
•Myopathic patterns – abnormal muscle EMG patterns
•Distinct patterns made by myasthenia gravis, ALS, myotonic dystophy

EMG
•Mononeuropathies and peripheral neuropathies also produce abnormal EMG patterns -> these conditions cause improperly innervated muscles to deteriorate
•May also help detect denervated muscles and help determine which peripheral nerve or nerve root is damaged

Serum Enzyme Determination
•Lactic dehydrogenase (LDH), AST, aldolase, CK escape into the bloodstream proportional to the muscle damage
•NMS produces the greatest increase in CK
•Also elevated in Duchenne muscular dystrophy patients, their fetuses, women carriers; metabolic and inflammatory myopathies
•Check CK first if patient has unexplained nonspecific weakness, myopathy, NMS

Muscle Bx
•Diagnose muscle disorder by biopsy for these diseases:
–Duchenne muscular dystrophy
–Polymyositis
–Trichinosis
–Collagen vascular disease
–Mitochondrial myopathies
–Rare glycogen storage diseases

Dx:
•Diagnose mitochondrial myopathies with electron and light microscopy
•Genetic testing is generally easier, accurate, informative however

Thermography
•Infared thermography performed on head, neck, lower spine, limbs
•Has little or no value
•Also not good for evaluation of herniate discs, HA, CVA