Neuromuscular disease (including some myelopathies) Flashcards
Metabolic myopathies
Most metabolic myopathies present as exercise intolerance (dynamic dysfunction).
Acid maltase deficiency (Type 2: Pompe) and Debranching enzyme deficiency (Type 3: Cori) are important exceptions presenting as myopathies with respiratory involvement (static dysfunction).
Axonal neuropathy
There is an overall loss of axons
– The cleared spaces (arrow) are where axons used to traverse.
– There are small groups of thinly myelinated axons indicating early phases of reinnervation (circle).
Demyelinating neuropathy
“Onion bulbing” due to chronic demyelination and remyelination
Seen in CMT, CIDP, HNPP
Tomaculae
Sausage-shaped focal swellings in the myelin sheath
Seen in HNPP
Target or targetoid fibers
Neuropathic muscle biopsy
Target or targetoid fibers, that are best observed with NADH-TR staining (for assessing oxidative enzymatic function in the muscle). Target fibers are characterized by the presence of three zones, each with varying stain intensity, within the cell. The pale central zone results from reduced oxidative enzymatic activity, disorganized myofibrils, and a paucity of mitochondria. The central zone is encircled by a darkly stained zone, that is enriched with mitochondria and has increased enzymatic activity. The third zone stains normally, and is at the periphery of the myofiber. T_arget fibers are most commonly type I muscle fibers (slow fibers)_
.
Angular fibers
Neuropathic muscle biopsy
The earliest structural change in neurogenic atrophy seen on muscle biopsy is the loss of the polygonal shape of the muscle fiber.(18) A pattern of scattered, atrophic muscle fibers involving both types I and II fibers is another early finding. The atrophic fibers become small and angulated.
Fiber type grouping
Neuropathic muscle biopsy
Clustering of type 1 or type 2 fibers
Occurs with re-innervation - if re-innervation occurs, fiber-type grouping will be evident with ATPase staining and the normal patchwork pattern will no longer be evident. Instead, groups of similar fiber-types will lie adjacent to one another. This phenomenon occurs after denervation followed by reinnervation, when a single remaining near-by motor neuron sprouts and re-innervates multiple atrophied muscle fibers, altering the fiber-type to reflect the metabolic signature of the re-innervating motor neuron.
Group atrophy
Neuropathic muscle biopsy
Refers to atrophy of groups of muscle fibers in which muscle fibers belonging to the same motor unit are simultaneously affected. The number of fibers affected within a group varies greatly (from less than ten to hundreds)
Inflammatory myopathies
Polymyositis
Inflammation between muscle fibers (endomysial) (circle). with muscle fiber invasion by lymphocytes (arrow).
Inflammatory myopathies
Dermatomyositis
Atrophy of muscle fibers around a fascicle (perifascicular) secondary to capillary inflammation (arrows).
Inflammatory myopathies
Inclusion body myositis
Characterized by serpentine vacuoles studded by amyloid protein inclusions (rimmed vacuoles) (circle).
May also see mild endomysial inflammation
Mitochondrial myopathy
– Subsarcolemmal accumulations of precipitated eosinophilic mitochondria (“ragged red fibers”) (circle).
– On enzymatic staining for cyclooxygenase, which is an essential enzyme in mitochondria oxidative phosphorylation, there are muscle fibers that lack this enzyme (arrow).
Muscular dystrophies - common features
Degenerating fibers/ regenerating fibers (necessary)
Fiber rounding, central nuclei, variation in fiber size (nonspecific)
Increased connective tissue (arrow) and fat (nonspecific).
Diagnosis based on enzyme testing or genetic testings
In Duchenne’s muscular dystrophy, there is severely reduced or absent staining for dystrophin in the muscle membrane (bottom).
Congenital myopathies
Nemaline rod myopathy - purple aggregates of muscle filament originating from the Z-lines
Congenital myopthy
Central core myopathy
Central clearing that runs the entire length of the muscle fiber
ALS
UMN+LMN signs in the absence of sensory symptoms or sensory abnormalities on examination.
A neurodegenerative disorder that affects motor neurons in the anterior horn of the spinal cord, but also the motor cortex and brainstem. Sporadic ALS affects men more than women. It can present at any age but with a peak incidence in the sixth to seventh decade of life.
MC progression - most often muscle weakness begins focally, usually in the extremities (two-thirds of cases) and spreads to involve contiguous regions.
The split-hand phenomenon is a feature of ALS, characterized by weakness and atrophy of the lateral hand (thenar and first dorsal interosseous muscles) with relative sparing of the medial hand (hypothenar) muscles.
Approximately one-third of patients present with bulbar symptoms, such as dysarthria or dysphagia (bulbar-onset ALS).
Pseudobulbar palsy can occur in ALS. Cognitive impairment of some degree is present in up to 50% of patients with ALS; it is mostly subclinical, but can be detected on neuropsychological testing. In a small protein of cases, cognitive dysfunction can manifest as dementia - typically FTD - and occurs most frequent in patients with bulbar-onset ALS.
The region of motor neurons in the sacral spinal cord that are responsible for sphincter control, Onufrowicz’s nucleus (also known as Onuf’s nucleus) is generally spared in ALS, and sphincter dysfunction is typically not a prominent problem. Sensory nerve involvement and dysautonomia are also uncommon in ALS although they can occur.
Progressive muscular atrophy
_LMN - a diagnosis of PMA is usually reserved for patients who have electrodiagnostic evidence of motor neuron disease and have isolated lower motor neuron findings at least 3 years from symptom onse_t.
It often presents with focal asymmetric distal weakness that later involves more proximal regions and other extremities, with lower motor neuron features on examination such as atrophy, hyporeflexia, and fasciculations. PMA begins at an earlier age as compared to ALS, and survival is often longer than ALS, with a median survival of 5 years though more rapidly progressive and more chronic forms of the disease occur.
Bulbar and respiratory symptoms occur later than in ALS
Laboratory evaluation may reveal moderately elevated creatine kinase, but never more than 10 times normal, and EMG shows evidence of motor neuron disease.
PLS - pathology
Autopsy in patients with PLS has shown significant cell loss in layer 5 of the motor and premotor cortex, predominantly the large pyramidal Betz cells with corticospinal tract degeneration.
Primary lateral sclerosis
UMN
Presence of upper motor neuron signs at least 3 years from symptom onset without evidence of lower motor neuron dysfunction. (The majority of ALS patients who present with predominantly upper motor neuron signs and symptoms eventually develop lower motor neuron involvement by 3 to 4 years.)
It typically presents in the sixth decade of life with a progressive spastic tetraparesis and later, cranial nerve involvement. Rarely, bulbar onset occurs. Spasticity, rather than muscle weakness or atrophy, is the most prominent feature. It typically progresses slowly over years. Autonomic involvement does not typically occur.
Treatment of PLS is symptomatic, and usually includes baclofen (a GABAB agonist) or tizanidine (an α2-agonist) to reduce spasticity.
Vs hereditary spastic paraparesis - will see a family hx in HSP and usually white matter changes on MRI brain and C-spine
Progressive bulbar palsy
UMN+LMN of bulbar segment
ALS - genetics
90% sporadic, 10% familial with 20% of familial secondary to mutations SOD1: Cu, Zn dimutase on chsm 21q22 with A4V MC mutation in North America
C9orf72 hexanucleotide expansion identified as the most common cause of genetic ALS (and mutations have also been identified in sporadic disease)
*Mutations also described in TDP-43, FUS, ANG, VCP, FIG4 and other genes
ALS - riluzole
Inhibits glutamate release
ALS and associated s(x)s
15-50% with frontotemporal dementia on exam
– Mutations in C9orf72, TDP-43, VCP and FUS also cause FTLD
ALS pathology
Bunina bodies: eosinophilic cytoplasmic incisions in the anterior horn motor neurons, specific for ALS
ALS pathology
Insoluble proteins in the cytoplasm of degenerating neurons: TAR DNA-binding protein (TDP-43) is major component of neuronal cytoplasmic inclusion and colocalizes with ubiquitin
Ubiquilin 2 colocalizes with pathologic inclusions as well
LMN disease - infectious causes
Poliovrus
Coxsackie A & B
West Nile Virus: flavivirus, can also cause meningoencephalitis and a GBS-like neuropathy that may be axonal or demyelinating
Enterovirus
Echovirus
Spinal muscular atrophy
AR, linked to chromosome 51, 2nd MC AR disorder
Has 4 types that are defined clinically but the phenotype predicts the genotype
Spinal muscular atrophy
AR, linked to chromosome 51, 2nd MC AR disorder
Has 4 types that are defined clinically but the phenotype predicts the genotype
SMA Type I
Werdnig-Hoffmann
– Onset usually by 3 months, always by 6 months
– Alert face and normal eye movements
– Death: 50% by 7 months, 95% by 17 months
SMA type 1, infantile SMA or Werdnig–Hoffman disease presents with decreased fetal movements, neonatal hypotonia, and weak cry. Patients with SMA type 1 exhibit head lag and frog-leg posture when supine, and are never able to sit up or achieve antigravity strength in the arms or legs. Diffuse areflexia is often present. Bulbar involvement leads to dysphagia, and respiratory involvement occurs. Death usually occurs by 2 years of age.
Gene-therapy for SMA: Zolgensma is indicated for the treatment of children less than two years of age with SMA. The product is an adeno-associated virus vector-based gene therapy that targets the cause of SMA. The vector delivers a fully functional copy of human SMN gene into the target motor neuron cells. A one-time intravenous administration of Zolgensma results in expression of the SMN protein in a child’s motor neurons, which improves muscle movement and function, and survival of a child with SMA.
SMA Type II
Dubowitz diseas
– Onset < 18 months, never stand independently
In SMA type 2, intermediate SMA, symptoms begin in the first 1 to 2 years of life, with motor delay and tremor in some cases. This form is less severe than SMA1, with most children being able to sit unsupported, but significant contractures develop, and most are not able to ambulate.
SMA Type III
Kugelberg-Welander
– Onset > 18 months, may walk
SMA type 3, juvenile SMA or Kugelberg–Welander disease, typically presents in childhood (between ages 5 and 15 years) with difficult walking. The clinical picture is one of proximal muscle weakness, a fine action tremor, and fasciculations. Patients often remain ambulatory into adulthood.
SMA Type IV
Adult onset
SMA type 4, adult-onset SMA or pseudomyopathic SMA, is the least common and least severe. Symptoms typically begin in the third to fourth decade of life, and include proximal muscle weakness, with the quadriceps being prominently involved, and fasciculations. Ambulation into late adulthood is common. Cranial nerve and respiratory involvement is rare.
SMA and SMN1 and SMN2
Telomeric SMN1 is mutated in 95% of SMA
SMN1 and SMN2 genes nearly identical but splicing causes production of different SMN protein, SMN2 skips exon 7
Copy # of SMN2 gene inversely related to severity of disease
Absence of SMN1 and SMN2 is lethal
Total amount of full length SMN protein is probably the best predictor of disease severity
X-linked BSMA - overview
Kennedy’s disease
Bulbospinal muscular atrophy
Male sex (1:50,000)
Cramps
Elevated CPK (<1000)
Facial myokymia
Gynecomastia
Impotence, infertility, testicular atrophy
NCS: reduced sural amplitudes
EMG: chronic denervation
X-linked BSMA genetics
Trinucleotide repeat (CAG) in androgen receptor gene Actually X-linked dominant with reduced penetrance in females because of lower testosterone levels Toxic gain of function of abnormal receptor causes hormone dependent neurodegeneration _– Androgen antagonist therapy has so far failed in clinical trials_
Acute demyelinating polyneuropathy
Inflammatory
- Guillain-Barré syndrome (GBS)
– Idiopathic/Postinfectious
– Parainfectious: HIV, HBV, EBV, CMV, Lyme, toxoplasmosis
– Associated with lymphoma
Toxic
– Diphtheria
– Buckthorn berry intoxication
Diphtheria
Acute demyelinating
GPR that produces an exotoxin->neuropathy, cardiomyopathy
Acute illness: nasopharyngitis, tonsillitis, laryngitis
Biphasic neuropathy
- Acute: local effects of toxin, palatal, and pharyngeal sensory loss with dysphonia and dysphagia
-8-12 weeks after infection: radiculoneuropathy that clinically resembles GBS
-Cardiac involvement 2/2 dysautonomia or myocarditis
*Antitoxin dec severity of neuropathy if given early
GBS
Acute demyelinating
May be preceded by minor infection: campylobacter jejuni, mycoplasma pneumoniae, Zika virus
May be preceded by vaccination or surgery
CSF shows Albumino-cytologic dissociation
Autonomic dysfunction
Common electrodiagnostic pattern: loss of median sensory with present sural sensory
Non-length-related
• IVIG, plasmapheresis equally effective, no role for steroids
Chronic demyelinating
Inflammatory: CIDP
Toxic: Long-list
Hereditary: CMT, HNPP, CMTX, Refsum, hereditary leukoencephalopathies
CIDP
Chronic demyelinating
S(x)s persisting beyond 8 weeks
Associated with paraproteinemia
– Monoclonalgammopathyof undetermined significance
– Waldenström’s macroglobulinemia IgMκ
– Osteosclerotic myeloma IgGλ or IgAλ
Associated with lupus, melanoma, HIV
Multifocal motor neuropathy
Chronic demyelinating
Male > female
Often presents with distal arm weakness in the distribution of a named nerve
Important differential diagnosis for ALS
Hallmark of diagnosis is conduction block in a motor nerve with normal sensory conduction through that segment
IgM directed against GM1 antibodies in 20-80%: these may also be found in patients with Acute Motor Axonal Neuropathy (AMAN)
• IVIG is first line therapy
Alo known as multifocal motor neuropathy with conduction block. This condition is a purely motor demyelinating neuropathy that presents with asymmetric weakness from involvement of individual peripheral nerves, hypo- or areflexia in the distribution of affected nerves, and no sensory manifestations. CSF studies show normal protein levels, in contrast to acute and chronic demyelinating polyneuropathies. Anti-GM1 antibodies have been detected in this condition, but the presence of these antibodies is not required to make the diagnosis, and does not predict response to therapy. Electrophysiologic testing demonstrates typical conduction block in various nerve distributions. The presence of conduction block is not, however, required to make the diagnosis if there are other features of demyelination, and response to treatment is not different between patients with or without conduction block. Sensory NCS are normal. Patients with MMN do not have a good response to steroids or plasmapheresis, and some may worsen with these therapies. The use of intravenous immunoglobulin has been shown to be of benefit and is associated with clinical improvement. Other therapies that have been reported to be beneficial are rituximab and cyclophosphamide.
Toxic demyelinating - chronic
Diphtheria (acute)
Buckthorn berry (acute)
Amiodarone
Hexachlorophene
Perhexilene
N-Hexane (glue sniffing)
Chloroquine
Procainamide
FK-50
CMT
Chronic/hereditary demyelinating
1A: AD, chromosome 17, PMP22 duplication where PMP is the intrinsic membrane protein of compact myelin
1B: AD, chromosome 1, MPZ mutation for myelin protein 0 gene
HNPP
Chronic/hereditary demyelinating neuropathy
Hereditary Neuropathy with Liability to Pressure Palsies: AD, chrom 17, PMP 22 deletion
CMTX
Chronic/hereditary demyelinating
X-linked, connexin 32 mutation, intermediate conduction velocities
Refsum’s disease
Chronic/hereditary demyelinating
AR, peroxisomal disorder with elevated serum phytanic acid, retinitis pigmentosa, cardiac failure
– Treat with low phytanic acid diet
Leukoencephalopathies with associated neuropaty
Chronic/hereditary demyelinating neuropathy
Metachromatic leukodystrophy: AR, chrom 22, arylsulfatase A
Krabbe’s Disease: AR, chrom 14, galactocerebroside β-galactosidase
Cockayne’s syndrome: AR, chrom 5, progeria-like syndrome
Acute axonal polyneuropathies
AMAN
Porphyria
Toxins
Tick paralysis
Chronic axonal polyneuropathy
Inflammatory and vascular: collagen vascular diseases, vasculitides, paraproteins, amyloidosis, cryoglobulins, sarcoidosis (with associated myopathy)
Metabolic/systemic disorders: diabetes, impaired glucose tolerance, celiac disease renal and hepatic failure, primary biliary cirrhosis, critical illness, hypothyroidism (also see in COPD, HLD, porphyria)
Nutritional - vitamin deficiencies: B12, E, Copper
Inherited: CMT2, Giant axonal neuropathy, SCA, ataxia-telangiectasia
Toxic - long list
Paraproteins in neuropathy
Amyloidosis
Chronic axonal neuropathy: inflammatory and vascular– Small fiber neuropathy, often painful
– Autonomic features prominent
– Carpal tunnel syndrome
– Cardiomyopathy, nephrotic syndrome – Amyloid is extracellular
• connective tissue and vessel walls
– Acquired
• Paraprotein, often λ light chain
• Multiple myeloma may be diagnosed later
– Hereditary
• AD, transthyretin mutation, chrom 18 • Liver transplant prevents progression
Cryoglobulinemia
Chronic axonal neuropathy: inflammatory and vascular
• Immunoglobulins that reversibly precipitate below body temperature (37°C)
• May be essential or associated with:
– Paraprotein +/- lymphoproliferative disease
• Waldenström’s macroglobulinemia, multiple myeloma
– Hepatitis C, HIV (RF often present)
– Connective tissue disease (mixed cryoglobulinemia)
• Can be multifocal mononeuropathy (pathology is vasculitis) or polyneuropathy
Celiac disease
Chronic axonal neuropathy: metabolic, systemic
• Gluten sensitive enteropathy: T-cellmediated immune response against ingested gluten
• Peripheral neuropathy
• Ataxia due to Purkinje cell loss
• IgA directed against tissue trans glutaminase and gliadin
• Intestinal biopsy is still gold standard
– Blunted intestinal villi, hyperplastic crypts, inflammation
• Treat with gluten-free diet
B12 deficiency
Chronic axonal neuropathy: nutritional
B12 (Cobalamin): neuromyelopathy
– Subacute combined degeneration
– Loss of fibers in posterior columns and lateral tracts
– Sensory>motor neuropathy, optic neuropathy
Other: dementia, megaloblastic anemia, glossitis
– If intermediate B12 (100-200), elevated methylmalonic acid → sucinyl co A in rxn with B12 and/or homocysteine →methionine confirm deficiency
– Causes
• dietary (vegetarians)
• deficiency of intrinsic factor (required to absorb vitamin B12), secondary to post-gastrectomy syndrome, pernicious anemia (antibody to parietal cells)
Serum methylmalonic acid and homocysteine levels should be obtained when following patients with B12 deficiency receiving treatment.
Vitamin E deficiency
Chronic axonal neuropathy: nutritional
E (α-tocopherol): large fiber sensory neuropathy with sensory ataxia
– Loss of fibers in posterior columns and dorsal root
– May occur in malabsorption syndromes (chronic bowel disease, cystic fibrosis)
– Also in A-β-lipoproteinemia
• Retinitis pigmentosa
• Acanthocytosis
• Treat with diet rich in medium chain triglycerides to replace fat
Copper deficiency
Chronic axonal neuropathy: nutritional
Neuromyelopathy
– Often seen with high zinc levels, should stop zinc supplementation
CMT2
Chronic/hereditary axonal neuropathy
AD, less common than CMT1, diverse genetic causes
Most common mutation: MFN2 which encodes mitofusin 2, an intrinsic membrane protein in mitochondria
Giant axonal neuropathy
Chronic axonal neuropathy: hereditary
Childhood onset with gait disorder, gigaxonin mutation
Spinocerebellar ataxia
Chronic axonal neuropathy: hereditary
AD, some with axonal polyneuropathy that is sensory or sensory-motor
Ataxia-telangiectasia
Chronic axonal neuropathy: hereditary
AR, defect in DNA repair
HIV and neuropathy
GBS: seroconversion, +cells inCSF
CIDP: also + cells in CSF
Mononeuropathy: consider herpes zoster
Mononeuritis multiplex/Polyradiculopathy – vasculitis, CMV, lymphoma
Axonal polyneuropathy, sensory > motor – Dysesthetic pain prominent
ALS variant
– Elevated CSF protein, improvement with AZT
Toxic: nucleosides (ddC,ddI,d4T,3TC)
– Dose-dependent, painful, sensory
Neurosyphillis
Meningovascular syphilis: Stroke syndromes
– Syphilitic endarteritis of the great vessels
– 5-12 years after untreated infection
General paresis: Neuropsychiatric symptoms
– Direct infection of the meninges and cortex
– 15-20 years after untreated infection
Tabes dorsalis: Neuromyelopathy
– Posterior columns of spinal cord and dorsal roots
– 18-25 years after untreated infection
– Gait ataxia, lightning pains,
Charcot’s joints
– CSF not always abnormal
Treatment: PenicillinG(IV)
Leprosy
Mycobacterium leprae: gram + acid fast rod
Infects cool areas: chin, malar face, ear lobes, buttocks, knees, lower legs
Tuberculoid: focal skin lesions
– Anesthetic, hypopigmented, hairless, dry
Lepromatous: more diffuse disease
Borderline: between tuberculoid and lepromatous
Treatment: depends on extent
Lyme disease
Ixodes tick transmits spirochete Borrelia
Erythema chronica migrans (painless)
Acute disseminated syndrome – Fever, arthralgias, myalgias,
headache, fatigue
Meningoradiculitis may occur – often painful – GBS-like acute neuropathy
Focal neuropathies (facial, plexopathies)
Chronic sensory-motor axonal polyneuropathy
AIDP variants
Miller-Fisher variant: ophthalmoplegia, ataxia, and areflexa; associated with anti-GQ1B antibodies
Facial diplegia with acral paresthesias: isolated LMN pattern facial weakness accompanied by paresthesias in the distal extremities and decreased or absent reflexes but without extremity weakness
Pharyngeal-cervical-brachial variant: dysphagia, neck weakness, proximal upper extremity weakness, and areflexia that is often limited to the upper extremities, and may also cause ptosis; anti-GT1a antibodies may be seen with this variant
AMAN - acute motor axonal neuropathy - and AMSAN - acute motor and sensory axonal neuropathy - are axonal variants
GM1, GM1b, GD1a, (and GalNac-GD1a for AMSAN)
Variants of CIDP
MADSAM - multifocal acquired demyelinating sensory and motor neuropathy: CIDP with sensorimotor asymmetric onset
DADS - distal acquired demyelinating symmetric neuropathy (associated with anti-MAG IgM), responds poorly to immunotherapy: CIDP but distally predominant
MMN - multifocal motor neuropathy: CIDP with asymmetric motor onset (GM1)
CISP - chronic immune sensory polyneuropathy: CIDP but sensory predominant
Small fiber neuropathies
Can have normal NCS/EMG
Metabolic: diabetes
Toxic: alcohol
Infectious: HIV, HCV
Inherited: Fabry’s disease, hereditary sensory and autonomic neuropathy, amyloidosis
Inflammatory: Sjogren’s syndrome, sarcoid, celiac, paraneoplastic: MC anti-Hu
LEMs
Pre-synaptic disease
Pathophysiology: Auto-antibodies against pre-synaptic voltage-gated Ca2+ channels on cholinergic neurons
Clinical s(x)s: proximal weakness, mild ptosis but bulbar s(x)s rare compared to MG, autonomic sxs: dry mouth (77%); some with constipation, blurred vision, and erectile dysfunction; reflexes and strength may increase briefly immediately after exercise
D(x): VGCC antibodies present in 90% in LEMS but low titer positive in up to 24% patients with cancer without LEMS, 23% of ALS patients and 3% in MG -> thus, VGCC antibody test is confirmatory only in those with the clinical and electrophysiologic features of LEMS; typical electrophysiology features on nerve conduction studies approach 100% sensitivity
LEMS and cancer
Pre-synaptic disease
About half have underlying malignancy: m_ostly SCLC – 85% in one series, 2/3 of men and 1/3 of women with malignancy_
– The remainder have autoimmune LEMS without cancer
Warrants repeat malignancy screening – CT C/A/P, mammogram, colonoscopy, prostate or GYN exam
– PET in smokers over age 50
– if not present at the diagnosis of LES, most tumors become evident within the first two years after onset of LEMS, nearly always w/in 4 years of LES onset
Botox - 3 forms
Pre-synaptic disease
Food borne (due to ingestion of the toxin of the Clostridium botulinum bacterium)
Wound botulism, usually in IV drug abusers (bacterium in the wound produces the toxin)
Infant botulism (due to ingestion of the bacterium spores that germinate in the infant GI tract)
- unlike the adult forms, C. botulinum can be cultured from the stool of infants with botulism
Botulism - pathophysiology
Presynaptic disease
Toxin is spread via the vascular system and binds to a specific receptor (synaptotagmin II) on the pre-synaptic side of peripheral cholinergic synapses at ganglia and neuromuscular junctions
After gaining entrance to the pre-synaptic cytoplasm, botulinum toxin binds irreversibly to intracellular SNARE proteins involved in acetylcholine (ACh) release*
Toxins A to G – A, B, E cause human disease
– Cleave SNARE proteins used in the docking and fusion of the ACh vesicles with the pre- synaptic membrane, preventing transmitter release
– Toxins A and E cleave SNAP-25 (synaptosomal-associated protein-25), type C cleavers syntaxin and toxin B cleaves synaptobrevin/vesicle-associated membrane protein (VAMP)
Some forms of congenital MG
Pre-synaptic disease
– some with infantile onset have genetic abnormalities in ACh packaging, re-synthesis or mobilization -> produces paucity of ACh vesicles or reduced quantal release
– should be considered if: a positive family history, a lack of responsiveness to acetylcholinesterase inhibitors, absence of AChR antibodies or a slow progressive course dating back to childhood
Severe hyperMg
Presynaptic disease
– competes with Ca2+ and interferes with ACh release
– often in patients with renal insufficiency who receive oral magnesium (e.g., laxatives) or during treatment for eclampsia
– ocular muscles spared
Tick disease
Pre-synaptic disease
– Toxin (not identified) blocks pre-synaptic sodium ion influx – prevents pre-synaptic terminal depolarization (i.e., no Ca2+ influx and no transmitter release)
– Ascending flaccid paralysis 3 to 7 days after tick attaches – diagnosis and treatment by finding and removing the tick
– Rocky Mountain wood tick, Lone Star tick, American dog tick, Gulf coast tick
MG - clinical
Post-synaptic disease
Patients present with complaints of specific muscle weakness and not generalized fatigue
Symptoms are best in the AM upon awakening; worsen late in the day, after exercise and in the heat
About 10% have underlying thymoma
Symptoms at onset:
~50% Ocular only: present with ocular manifestations (ptosis and/or diplopia) - most develop ocular symptoms at some point -> up to 50% of these remain ocular only, ocular MG, of other 50% that progress to general, 75% by 1 year of symptoms, 85-90% by 2-3 years
35% Mix of ocular, bulbar, neck and/or limb weakness
15% Bulbar only
Uncommon - isolated neck weakness or isolated respiratory only
From Ching-Ching: Ocular muscles are most commonly involved, with ptosis and diplopia as the presenting symptom in 70% to 90% of cases. Up to 80% of such patients generalize to involve bulbar, limb, neck, and/or respiratory muscles within 2 years. In a minority (10% to 15%), involvement remains restricted to the eyes, so-called ocular myasthenia.
MG - antibodies
Post-synaptic disease
Generalized myasthenia gravis
– Auto-antibodies to ACh receptor (AChR) in most (80-85%)
– One third to 1⁄2 of those MG patients without AChR antibodies have antibodies instead to muscle specific receptor kinase (MuSK)
–The remaining ~10%, without demonstrable serum antibodies are termed “seronegative”
(Maybe outdated)
Ocular MG
– ~50% have positive AChR antibody titers
– None have MuSK titers
– So, ~50% of OMG are seronegative
MG - congenital symptoms
Post-synaptic
– endplate acetylcholinesterase deficiency (produces depolarizing block!)
– genetic defects of the AChR
slow channel syndrome
receptor deficiency
deficiency of associated proteins (rapsin or plectin)
Acute organophosphate toxicity
Post-synaptic disorder
Exert their NMJ toxicity by the irreversible inhibition of acetylcholine cholinesterase (AChE)
– produces excess ACh at the NMJ
– excessively depolarizes the postsynaptic membrane
– this impairs activation through persistent depolarizing block
– produces weakness as well as autonomic and central nervous system dysfunction (altered sensorium often key – not seen in other NMJ disorders)*
Overdose or ingestion of certain pesticides
Agents of war – inhibit the hydrolysis of Ach by AChE by binding to and phosphorylating the active sites of AChE
V – series (V = venomous) more potent – e.g., VX (venom X)
G – series (G = German) – e.g., GB (sarin)
Non-depolarizing neuromuscular blocking agents
– In patients with MG or LEMS may have excessive effect
– Historical: curare (d-tubocurarine) occupies the same position on the receptor as ACh with an equal or greater affinity - a competitive antagonist
– Used in anesthesia, such as vecuronium, atracurium, pancuronium
D-penicillamine and MG
Produces autoimmune MG with ACh receptor antibodies
Slowly resolves after discontinuation of the med
Low frequency RNS for NMJ disorders
RNS at 2-3 Hz x6-10 times
Normal muscles: No change in CMAP amplitude with repetitive nerve stimulation
Myasthenia gravis or pre-synaptic disorders
– Progressive decline in CMAP amplitudes with the first 4 to 5 stimuli.
– Positive RNS test features
Decrement in CMAP amplitude
– Size: More than 10% in reduction in CMAP amplitude
Measure from 1st to 3rd, 4th or 5th potential in train (whichever is smallest)
[] Also see post-exercise (tetanic) potentiation and exhaustion
Also see decremental response at low frequency RNS in pre-synaptic disorders
Sensitivity and specificity for RNS
Sensitivity of RNS for MG is reduced when only distal muscles are tested (~ 50% recording from the hand to 90% with addition of recording from the trapezius, biceps, or face)
MuSK-positive patients - higher yield with facial nerve RNS
Important: If median or ulnar studies are normal, do proximal nerve (e.g., spinal accessory) and facial nerve
RNS is only + in 15-45% of patients with ocular MG
High-frequency RNS for NMJ disorders
Incremental responses (>100%)
– With high frequency RNS 30-50 Hz, or
– Immediately after 10-20 seconds of maximal exercise
These features (low resting CMAP amplitudes and incremental responses after exercise) are not present in myasthenia gravis or other post- synaptic NMJ disorders
Why?
– Due to transiently increased concentration of calcium in the pre-synaptic terminal
– This increases the number of ACh quanta released with each pre-synaptic action potential
– This also underlies the brief clinical facilitation of reflexes and strength after brief exercise in LES
RNS summary
RNS Studies: summary*
When a decremental response is present at 2-3 Hz RNS
– Correlate with the needle EMG exam
– CMAP amplitude at rest and immediately after exercise
Postsynaptic NMJ disorder, such as MG
– Needle EMG shows no signs of active denervation – No increment in the CMAP after exercise
Presynaptic NMJ disorder, such as LEMS
– Needle EMG shows no signs of active denervation – Increment >100% in the CMAP after exercise
Single fiber EMG
Simultaneously records potentials of two muscle fibers innervated by an individual axon
– Measures this variability = “Jitter”
– SFEMG is the most sensitive test for MG and LEMS
NB: AChR or MuSK antibodies are most specific test for MG
– Abnormal jitter is not specific for MG
May occur in other neuromuscular disorders, including ALS, polymyositis or LEMS
MG and LEMS sensitivity and specificity of tests
The sensitivity of serum AchR binding antibodies is highest for generalized myasthenia, detecting antibodies in 70% to 95% of patients and lower for patients with ocular myasthenia. Patients who are initially seronegative for binding, blocking, or modulating antibodies may seroconvert later in the course of their disease. In a minority of patients with autoimmune myasthenia in whom the binding antibody is not detectable, modulating or blocking antibodies may be present.
In approximately half of all patients who are seronegative for antibodies against the acetylcholine receptor, anti–muscle-specific tyrosine kinase antibodies are present
MG treatment
Myasthenia gravis:
Symptomatic treatment
– pyridostigmine (Mestinon®)
Immunotherapies
– prednisone
– azathioprine, mycophenolate mofetil, cyclosporine/tacrolimus
Rapid therapies
– Plasma exchange – IVIG
Thymectomy
Other cholinesterase inhibitors
Oral: Neostigmine bromide (Prostigmin®) - 1⁄4 dose of pyridostigmine
Parenteral: Pyridostigmine bromide - 1/30-1/60th the oral; (1-2 mg), Neostigmine methylsulfate: rarely used, 0.5 mg, Edrophonium (Tensilon®) - short-acting
Pryidostigmine
Advantages
– Few serious side effects
Disadvantages
– Effective minimally in many patients – Bothersome cholinergic side effects
Cholinergic side-effects
– Muscarinic: salivation, stomach cramps, diarrhea – Nicotinic: faciculations, muscle cramps
Treatment of side-effects
– Imodium, Lomotil
– Robinul (glycopyrrolate), atropine
Thymectomy in MG
In patients with thymoma:
Indicated in all with thymoma
– Important: Chest CT scan, or MRI, mandatory in all patients diagnosed with myasthenia (~10% have underlying thymoma)*
In patients without thymoma:
No randomized, prospective controlled studies – One currently in process
Probably beneficial in most
– Under age 60 with generalized disease
Thought to have a slow onset of action – Generally 2 years or longer
Treatment of botulism
Botulism
Supportive care: Ventilatory support
Antibiotics for C. botulinum bacterium
Not for food bourne – toxin ingested, not bacterium
Not for infant botulism – may cause lysis of the bacterium and dump toxin into gut increasing absorption
Used for wound botulism
Equine serum heptavalent (A-G) botulism antitoxin for adult botulism (food-borne or wound)
Best if used w/in 24 hours – from the CDC only via State Health Departments (also, poison control centers); Reduces mortality, even if given later in the course
20% serum sickness and 3% anaphylaxis (since
derived from horse serum)
Human derived botulism antitoxin for IV use in infants less than 1 year of age (babyBIG)
Sooner the better; w/in 3 days of hospitalization best
LEMs treatment
Symptomatic therapy – 3,4 DAP is considered first line therapy
3,4-diaminopyridine (3,4-DAP) - prolongs depolarization of the pre-synaptic membrane after a nerve impulse, increases influx of calcium, and increases acetylcholine receptor release
– Blocks pre-synaptic voltage-dependent potassium channels
– Not yet approved in US (can get for compassionate use)
– May cause seizures at high doses or in patients with seizure disorders
Pyridostigmine (Mestinon®) – marginally effective, best when used with 3,4-DAP
Immunotherapies
Same approach as with myasthenia
Prednisone
Rapid therapies: IVIG and plasma exchange
Chronic immunotherapies: Azathiopine, mycophenolate mofetil, cyclosporine/tacrolimus
PLEX
Effective in MG, LEMS, CIDP, GBS, Isaac’s syndrome
Used in certain paraprotein-associated neuropathies, Stiff-man syndrome, with questionable efficacy
Not effective in multifocal motor neuropathy (MMN) or inflammatory myopathies (polymyositis, dermatomyositis)
Works presumably by removing auto-antibodies and cytokines
Reduces immunoglobulin levels rapidly but these rebound within weeks if no concurrent immunosuppression
Considerations:
5 exchanges over 10-14 days for most
More effective if done every other day than daily
Reduces immunoglobulin levels rapidly but these rebound within weeks if no concurrent immunosuppression
Short onset of action (3-10 days)
Adverse effects: hemodynamic disturbances, infections, sepsis and other line complications
IVIG
Controlled trials show effective in MG, LEMS, GBS, CIDP, MMN
In some patients with inflammatory myopathies (PM, DM); IgM associated neuropathy; stiff-man syndrome
Not effective in IBM; most patients with paraprotein-associated neuropathy
Multiple mechanisms: competition with autoantibodies (anti-idiotype effect), inhibits cytokines, inhibits complement deposition, blocks Fc receptors on macrophages and immunoglobulins on B cells
Considerations
– Usual initial dose is 2 g/kg over 2-5 divided daily doses
– Maintenance dose is generally 1-2 g/kg every 3-6 weeks, depending on the clinical response
Adverse effects
– Common: headache, chills, flu-like sxs, fluid overload – Less common: rash, aseptic meningitis
– Serious: acute renal tubular necrosis (usually reversible), thromboembolic events (DVT, PE, MI, stoke), anaphylactic reactions (in those with IgA deficiency)
Immunotherapy in NMJ disorders
Quicker acting, shorter term use – Corticosteroids
Slower acting, long-term use
– Azathioprine (Imuran®)
– Cyclosporine and tacrolimus
– Mycophenolate mofetil (CellCept®) – methotrexate
Less commonly used
– Cyclophosphamide
– Rituximab
Corticosteroids
Prednisone: most commonly used drug
Advantages: short onset of action (0.5 to 2 months), can be used during pregnancy, inexpensive
Adverse effects: numerous
Data supports effectiveness in some inflammatory myopathies (PM and DM), MG, CIDP
Not effective in GBS, MMN, and most paraprotein- associated neuropathies
_High-dose daily (1 mg/kg) use is best in most; every other day dosing is often not adequate for initial clinical respons_e
Important exception is MG ! (unless concomitantly treated with IVIG or plasmapheresis)
– Transient paradoxical worsening occurs 5 to 10 days after the initiation of high-dose corticosteroids – serious in 50% and respiratory failure in up to 10%
This transient worsening is prevented by the quick onset of action of the rapid therapies
Azathioprine
Purine analogue that suppresses the activation of Rac1 target genes (interferes with T- and B-cell proliferation) – primarily T cell apoptosis
- Used most often in MG; only demonstrated effective in MG +/- inflammatory myopathies
- Doses 1.5-2.5 mg/kg daily
Pretreatment – suggest checking TMPT (thiopurine methytransferase) enzyme levels in serum-> if homozygous negative for TMPT (1 in 300) should not receive drug – develop severe bone marrow toxicity
Onset of action is slow – > 8 months: may not achieve peak effectiveness for 1.5 to 2 years
Side-effects:
Anemia/leukopenia* – dose related
Liver function abnormalities* (should not use with allopurinol that may greatly worsen this effect)
Flu-like reaction in 10 to 20 %
Small increased risk of non-Hodgkins lymphoma and non-melanotic skin cancer – not yet demonstrated in neurologic use
*follow CBC and LFTs monthly x 6, every other month x 6, and then quarterly
Cyclosporine
Inhibits predominantly T-lymphocyte-dependent immune responses
– Reduced synthesis of NFAT and IL-2 – Same mechanism as tacrolimus
Shorter onset than azathioprine (1-3 months)
Effective in MG; some benefit in CIDP and DM
Doses 2 to 2.5 mg/kg BID – aim for low theraleutic level for chronic renal transplant or lower
Serious side-effects
Nephrotoxicity* – uncommon with neurologic doses (5 mg/kg qd in two divided doses) and monitoring of trough drug levels and renal function studies
Hypertension* – treat aggressively; potentiates the nephrotoxicity
Interacts with many other drugs*
Especially avoid NSAIDs and nephrotoxic drugs
*monitor renal function, BP, trough levels
MMF
Selectively blocks purine synthesis in lymphocytes - inhibits their proliferation
Favorable experience in case series in MG, CIDP, PM
RCTs in MG do not show superiority of MMF and prednisone over prednisone alone – but the studies performed are limited by short period of treatment (3 and 9 months, respectively)
Well tolerated with few side effects
Side effects – anemia, possible low risk for late malignancies
Methotrexate
Antagonist of folate metabolism
Most commonly used in inflammatory myopathies (PM and DM); may be helpful in some patients with CIDP and MG (but experience is limited outside of PM and DM)
Acts faster than azathioprine
Dosing is often 2.5 mg every 12 hours times 3 per week (total weekly dose 7.5 mg); increased as needed by 2.5 mg per week to max of 25 mg per week in 3 divided doses given 12 hours apart
Adverse effects: Pneumonitis (more common with IV dosing), stomatitis, GI symptoms, leukopenia, hepatotoxcity – hepatic fibrosis may not be heralded by LFT abnormalities; with chronic use may need liver biopsy for monitoring
Framework for muscular disease
Dystrophinopathies
Muscular dystrophy
Most common form of MD
Dystrophin encoded on X-chromosome
– Large protein with high spontaneous mutation rate (1:10,000) found in skeletal and cardiac muscle
Mutations cause:
– Duchenne MD: <3% normal dystrophin
– Becker MD: reduced quantity of abnormal dystrophin – Dilated cardiomyopathy +/- muscle involvement
– Milder phenotypes: exercise-induced cramps/myalgias – Manifesting females: CPK, cardiomyopathy
Duchenne MD - genetics
Muscular dystrophy
X-linked
1:3300 live male births
30% new mutations • Frameshift mutations
This patient has Duchenne muscular dystrophy. This condition is a dystrophinopathy, inherited in an X-linked recessive fashion, and is the most common genetic muscle disease, affecting 1 in 3,500 live male births. About a third of the cases are caused by spontaneous mutations in the dystrophin gene, so there may not be a positive family history.
DMD clinical
Muscular dystrophy
Delayed motor milestones
Proximal weakness
Lordotic, waddling gait
Gower’s sign
Hypertrophy of calves, gluteals, lateral vasti, deltoid, infraspinatus
Loss of ambulation in preteen years (~11)
CPK elevated from birth
Progressive contractures
Non-progressive mental retardation frequent
Cardiomyopathy: sinus tach early, heart failure late concomitant with respiratory failure with pulmonary hypertension
Scoliosis, onset with loss of ambulation
This condition presents early in life and manifests with weakness and delayed development of motor milestones. These children have frequent falls, and difficulty walking, running, and rising from supine and sitting positions. Weakness is significant in the proximal muscles, predominantly in the iliopsoas, quadriceps, and gluteals, as well as the shoulder girdle and upper limbs. It also tends to affect the pretibial muscles. These patients have pseudohypertrophy of the calves due to fibrosis. They also have scapular winging and contractures. Ocular, facial, and bulbar muscles are usually spared. Cardiac involvement includes arrhythmias, cardiomyopathy, and heart failure. It is recommended that all patients with Duchenne muscular dystrophy undergo cardiac evaluation, even if asymptomatic from a cardiac standpoint. Mild developmental delay with a subnormal intelligence quotient (IQ) may be seen. These children become wheelchair or bed-bound, and may eventually die of respiratory failure and pulmonary infections.
Creatine kinase values range from 10 to 100 times higher than normal. Needle EMG shows fibrillations, positive waves, and myopathic motor unit potentials. Muscle biopsy show endomysial fibrosis, loss of muscle fibers with residual fibers of different sizes, some of which are very large and eosinophilic, and others very small and atrophic. Degeneration and regeneration, as well as necrosis and macrophage invasion, may also be seen. he diagnosis of Duchenne muscular dystrophy is made by genetic testing of the dystrophin gene or by absent dystrophin immunostaining on muscle biopsy.
Dystrophin stain in DMD
Muscular dystrophy
DMD treatment
Muscular dystrophy
Corticosteroid treatment prolongs ambulation
– This is based on non-randomised data but has become standard of care
Antisense oligonucleotide-induced exon skipping – converts a Duchenne phenotype to a Becker phenotype
– Largest trial on a drug that skips exon 51 – (13% of DMD patients)
Becker
Muscular dystrophy
Most mutations are in-frame deletions
Variable clinical severity
• Clinical onset usually > age 7
• Low-Average IQ
• Cardiac involvement may predominate, degree is not predicted by muscle weakness
– Obligate female carriers should be screened for cardiomyopathy
However, patients with Becker’s muscular dystrophy present later in life, sometimes in childhood, but more frequently in adolescence or adulthood. Given the milder phenotype, these patients are able to ambulate beyond the second decade of life, cardiac involvement occurs but is less frequent, and intelligence quotient (IQ) is usually normal. Needle EMG shows fibrillations, positive waves, and polyphasic short motor unit potentials. The biopsy will detect similar findings as in Duchenne muscular dystrophy (see questions 19 and 20); however, dystrophin is not absent in Becker’s muscular dystrophy, but structurally abnormal or present in a smaller than normal amount.
Myotonic dystrophy - clinical
Muscular dystrophy
Autosomal dominant, trinucleotide CTG repeat (chrom 19,myotonic dystrophy protein kinase gen aka DMPK gene)
– Probably due to aberrant regulation of alternative RNA splicing
Present early in adult life: Ptosis with facial weakness, Early limb weakness is mild and distal vs DM2 which is proximal, Myotonia: slow relaxation of voluntary muscle contraction, abates with continued activity
Other features: Cognitive changes: apathy, inertia, Central hypersomnolence
Cataracts: multicolored subcapsular opacities
Cardiac conduction defects
– Must avoid pro-arrhythmic meds for myotonia (quinine, procainamide, +/- dilantin); choose mexiletine if treatment absolutely necessary
Gonadal failure: testicular atrophy
Pregnancy complications
Frontal baldness, atrophy of the masseters and temporalis
Myotonic dystrophy - labs, EMG and pathology
Creatine kinase levels may be slightly elevated. EMG demonstrates myotonic discharges and short, sharp, early recruiting motor unit potentials with fibrillations. Histopathologically, muscle biopsy demonstrates marked central nucleation, type 1 fiber atrophy, peripherally placed sarcoplasmic masses, ring fibers, and pyknotic nuclear clumps.
Myotonic dystrophy - medication considerations
Muscular dystrophy
Anesthesia Considerations
– Induction with depolarizing relaxants (succinylcholine) and reversal (neostigmine) may worsen myotonia (no clear increase in malignant hyperthermia)
Apnea risks
– Benzodiazepines, barbiturates, opiates
Congenital myotonic dystrophy
Muscular dystrophy
Early childhood version of myotonic dystrophy
Proximal Myotonic Myopathy (aka PROMM or DM2)
Muscular dystrophy
Autosomal dominant CCTG expansion (chrom 3, ZNF9 - an intron of the zinc finger protein 9 gene on chromosome 3q, and it is associated with intranuclear accumulation of the expanded RNA transcripts)
Weakness is proximal
Face is usually spared
Clinical myotonia may be absent
Cataracts
Cardiac conduction defects
It is autosomal dominant and is characterized by myotonia and proximal muscle weakness (as opposed to the distal weakness characteristic of DM1, discussed in question 12). Cataracts and cardiac involvement also occur less commonly in DM2 compared to DM1. Histopathologic findings include muscle fiber size variability, many fibers with multiple (5 to 10 or more) internalized nuclei, and atrophic fibers with nuclear clumps.
Emery-Dreifuss muscular dystrophy
Muscular dystrophy
Early contractures of biceps, gastrocnemii: flexes the knee (and foot), posterior cervical muscles (elbows, ankles, and neck)
Slowly progressive weakness starts humeroperoneal
Cardiomyopathy: conduction defects leading to complete heart block and atrial paralysis
– Pacemaker, defibrillator, anticoagulation, transplant
• EMD1: X-linked - mutation in gene encoding protein emerin: nuclear membrane protein
• EMD2: AD (rarely AR) - mutation in gene encoding lamins A and C: nuclear membrane proteins
– Cardiac abnormalities prominent
– Relatively mild limb-girdle weakness – Contractures less prominent
– Allelic with LGMD1B (chrom 1)
Muscle weakness tends to affect the upper arms and shoulder girdle muscles first and later the pelvic girdle and distal leg muscles. There is no pseudohypertrophy of the calves, and intelligence quotient (IQ) is normal. Cardiac involvement is prominent, with serious conduction abnormalities, often requiring pacemaker placement.
Facioscapulohumeral muscular dystrophy (FSHD) - genetics
Autosomal dominant fashion and is caused by deletions in a 3.3 kb repeating sequences, termed D4Z4, located on chromosome 4q35.
Fascioscapulohumeral dystrophy - clinical
Muscular dystrophy
Face – transverse smile, no straw/whistle, weak eye closure
Scapular fixators (latissmus, rhomboids, serratus anterior, lower trapezius), leads to upriding trapezius
Pectoralis – reversal of crease Biceps > triceps, deltoid spared Tibialis anterior (foot drop)
Pelvic girdle with abdominal weakness and protuberance
Asymmetric, stepwise progression
No convincing cardiac features
Sensorineural hearing loss for high tones
Asymptomatic retinal telangiectasias
Albuterol – increased muscle mass but no increase in strength
FSHD is slowly progressive, and predominantly affects the face and shoulders, though later in the course of the disease, the lower extremities are affected as well. These patients have weakness that can be asymmetric, and present with difficulty lifting their arms above their head, with prominent involvement of the upper arms (scapular muscles, biceps, triceps, trapezius, serratus anterior, and pectoralis), with relative sparing of the deltoids. The upper arm seems to be more atrophic than the forearms, making the bones of the shoulder appear prominent. Weakness of the abdominal muscles produces the “Beevor sign,” in which the umbilicus moves upward with neck flexion.
Cardiac involvement is rare and intelligence is typically normal. Creatine kinase levels are normal to slightly elevated.
Age of onset is on average 16 in males and 20 in females, but can be variable, ranging between the first and sixth decades of life.
Oculopharyngeal Muscular Dystrophy
Muscular dystrophy
Autosomal dominant
Late onset
Chrom 14
Short expansion in the PABPN1 gene
Muscle biopsy: rimmed cytoplasmic vacuoles (variation in fiber size, intranuclear tubular filaments)
EM: tubulofilamentous nuclear inclusions that contain PABPN1 proteins
Ptosis and dysphagia, later weakness of proximal, facial and extraocular muscl
Autosomal dominant late-onset muscular dystrophy with manifestations restricted to the ocular and pharyngeal regions. It is more frequent in patients of French-Canadian descent, and is caused by a GCG (GCN where N can be A/T/G/C, MC G) repeat expansion in the poly-A–binding protein 2 gene on chromosome 14q11
Muscular dystrophy and cardiomyopathy
Hereditary inclusion body myopathy
Non-inflammatory
Mild or no elevation of CPK
Skeletal muscle affected only
Distal muscles affected early
Onset in teens or early adult life
AR or AD
Rimmed vacuoles (not specific)
Tubulofilamentous inclusions on EM (thicker than those in OPMD)
Polymyositis and dermatomyositis - clinical
Inflammatory myopathy
Proximal weakness: quadriceps, posterior neck
Dysphagia common
Cardiac: arrhythmia, dilated CM
Pulmonary: interstitial lung disease, respiratory muscle weakness (restrictive deficit)
– Associated with Jo-1 antibody (an antisynthetase antibody)
Overlap syndromes with collagen-vascular diseases (SLE, RA, Sjogren’s, MCTD)
Association with malignancy
Much higher in DM, age > 40 and men
Cancer diagnosis highest in first 2 years
Carcinoma: ovary & stomach overrepresented
DM more common in children
Steroid responsive (and other immunosuppressants)
Drug induced by D-penicillamine (treats RA), same as MG
Polymyositis pathology
Inflammatory myopathy
An inflammatory infiltrate composed of lymphocytes and macrophages surrounding muscle fibers. There are regenerating and necrotic fibers. These findings are characteristic of polymyositis, and neither rimmed vacuoles nor perifascicular atrophy is seen.
Perivascular infiltration, perimysial, endomysial inflammation
Dermatomyositis pathology
Inflammatory myopathy
Also with perivascular inflammation, but no perimysial or endomysial inflammation
Key is perifascular atrophy
Inclusion Body Myositis - clinical
Inflammatory myopathy
Most common inflammatory muscle disease after age 50, male > female
Finger flexors, quadriceps, biceps, triceps, iliopsoas, tibialis anterior
Dysphagia in 30%
CPK < 1000
Treatment refractory
Inclusion body myositis - pathology
Inflammatory myopathy
Endomysial inflammation (like polymyositis), groups of atrophic fibers, and i_ntracytoplasmic vacuoles with granular material known as rimmed vacuoles_, which are characteristic of inclusion body myositis.
HIV myositis
Inflammatory myopathy
HIV PM
HIVI BM
HIV necrotizing myopathy
HIV nemaline myopathy
AZT (zidovudine) myopathy – mitochondrial myopathy with ragged red fibers
Congenital myopathies
Structural change in the muscle fiber
No degenerating and regenerating fibers vs dystrophies
Early onset with hypotonia and weakness
Genetic basis
Non-progressive
Nemaline myopathy
Nemaline Myopathy
Muscle fibers contain rod-shaped structures
Mild, moderate and severe forms
AD, AR or sporadic
• Facial weakness sparing extraocular muscles
• Spares the heart
• May be a secondary finding (HIV myopathy)
Central core myopathy - clinical
Mutation in ryanodine receptor (chrom 19, same as myotonic dystrophy)
Associated with malignant hyperthermia
AD most common, parent often clinically unaffected
Ambulation usually achieved
Skeletal deformities, cramps common
Respiratory and cardiac involvement uncommon
Central core myopathy - pathology
Anesthesia and myopathy
In general prefer _non-depolarizing muscle relaxants_ _Avoid succinylcholine (depolarizing relaxant)_ _Avoid halothane, associated with malignant hyperthermia_
HMG-CoA reductase inhibitors myopathy
Inc risk with enzyme (CYP34A) inhibitors: cyclosporine, gemfibrozil, erythromycin, nicotinic acid, antifungals
May also be associated with increased risk of neuropathy
Steroid myopathy
Acute (critical illness myopathy): in combo with neuromuscular blocking agents (pancuronium), severe quadriplegia with respiratory involvement
Chronic: unlikely with doses < 10 mg daily, also seen in endogenous Cushing disease
Myotonia congenita
Three types
Thompsen - AD, in infancy, mild (painless) myotonia and hypertrophy but no weakness
Becker’s - AR, onset at 4-12 yo, more severe myotonia with associated weakness, muscle hypertrophy, “Herculean” phenotype
Myotonia levior: AD, later onset, mild myotonia, no muscle hypertrophy
Extreme muscle stiffness due to delay relaxation
“Warm up”, stiffness subsides with repeated muscle contraction
Allelic in CLCN1, a muscle CL channel
The main manifestation is myotonia, which is an impaired muscle relaxation as seen when the patients cannot relax their handgrip after grasping an object, and also manifested on percussion, leading to contraction and delayed relaxation. Myotonic potentials can be detected on EMG.
Propofol and depolarizing neuromuscular blocking agents may aggravate the myotonia, and patients may have prolonged recovery. Mexiletine is the treatment of choice.
Paramyotonia congenital
AD, Na channel mutations, allelic with the periodic paralyses
Similar to MC, failure of relaxation after muscle contraction
BUT
Temperature sensitive stiffness, may experience periodic paralysis
Provoked by cold
No “warm up” phenomenon. In fact, myotonia worsens with repeated muscle action
Typically more limited to forearm and facial muscles
This patient has paramyotonia congenita, which is an autosomal dominant channelopathy caused by a mutation in the sodium channel gene SCN4A. The manifestations are similar to those of myotonia congenita; however, unlike in myotonia congenita, in paramyotonia congenita, there is no “warm-up” phenomenon. Rather, repeated exercise accentuates myotonia, which is most clearly appreciated in the eyelids. Hence the name is derived from “para”-doxical reaction to exercise. Exposure to cold worsens the myotonia and may precipitate weakness, also in contrast to myotonia congenita. Percussion myotonia is rare, but can be seen after exposure to cold. EMG after cold exposure can also demonstrate fibrillation potentials followed by electrical inexcitability.
Hypokalemic periodic paralysis
AD, reduced penetrance, more common in males 3:1
Ca (type 1) and Na (type 2) channel mutations
Onset at any age, typically second decade
Can be provoked by low K, carbohydrate load (can trigger it via glucose load in clinical testing), alcohol, heavy exercise, cold, and emotional stressors
Attacks typically begin in AM, proximal>distal affect, respiratory muscles not affected, low serum K during attack, may have elevated CK
Weakness persists for hours with mild residual weakness for days
Type 1 is the dihydropiridine receptor (CACNA1S)
Tx: avoid triggers; carbonic anhydrase inhibitors such as acetazolamide and potassium-sparing diuretics are also useful in treating this condition.
Hyperkalemic period paralysis
AD, highly penetrant
Na channel mutation (like hypoK PP type 1 and paramyotonia congenita) - SCN4A
Provoked by high K (provocative testing with administration of K), rest after heavy exercise, fasting (hot and cold temperatures)
Onset commonly in infancy or childhood
Attacks one on quick, milder, briefer than hypoK variety <1 hr, serum K is typically normal
Residual weakness not typical
Treatment is focused on avoiding triggers. During attacks, glucose can be provided, and as prophylactic therapy, thiazide diuretics can be used.
Steroid-induced myopathy
Caused by chronic use of exogenous corticosteroids or by endogenous hypercortisolism,. Mild or moderate and proximal weakness.
Needle EMG findings are non-specific and creatine kinase levels are usually normal.
Histopathologically, there is atrophy of type II fibers. Management of this condition involves treatment of the underlying cause in case of endogenous hypercortisolism or reduction of exogenous steroids, as well as physical therapy.
Centronuclear myopathy
3 clinically different forms: (1) a slowly progressive infantile/early childhood type, (2) a severe X-linked neonatal type, and (3) an adult-onset type.
Presents with hypotonia and weakness at birth, or in early childhood, and unlike other forms of congenital myopathy, there is ptosis and ocular palsies, as well as weakness of facial, pharyngeal, laryngeal, and neck muscles. Proximal and distal weakness and hyporeflexia can be seen. Severe forms may be fatal due to respiratory failure in the first few months of life, but in some cases respiratory involvement is mild and/or delayed. Creatine kinase levels are mildly elevated. Needle EMG shows a myopathic pattern with positive waves and fibrillations. Pathologically, there are small muscle fibers and central nucleation, as well as predominance of type I fibers, which are small and hypotrophic.
Myotubular myopathy is the most common form of centronuclear myopathy and is X-linked. It is typically severe and presents in the neonatal period. The autosomal dominant form is an adult-onset milder form, and the autosomal recessive form is intermediate in severity.
MG demographics
Age of onset is bimodal for both men and women. For women the peak incidence is at age 20 to 24 and 70 to 75 years, while men have peak incidence at 30 to 34 and 70 to 74 years. In the early-onset group the female to male ratio is 7:3 and in late-onset it is 1:1.
MG and other autoimmune disorders
Myasthenia gravis is more common in family members of patients with this disorder. It has been associated with human leukocyte antigen types B8, DR1, DR2, and DR3. Patients with myasthenia gravis are at an increased risk of other autoimmune disorders including thyroid disorders, and these should be tested for as clinically indicated.
.Types of antibodies in MG
Over 80% to 85% of patients with myasthenia gravis have acetylcholine receptor antibodies, which have an affinity to the postsynaptic acetylcholine receptor and can be binding, blocking, or modulating.
The most commonly detected are the binding type. These antibodies cause complement-mediated destruction of the junctional folds that contain dense concentrations of this receptor, and a higher rate of internalization and destruction of acetylcholine receptors. Blocking antibodies might block binding of acetylcholine to its receptor at the neuromuscular junction, while modulating bind to a site on the receptor other than the acetylcholine binding site and alter the structure of the active site.
Tensilon test
Edrophonium is an intravenous acetylcholinesterase inhibitor that increases the presence of acetylcholine at the neuromuscular junction (NMJ). In patients with myasthenia, administration of edrophonium leads to transient improvement of weakness within minutes of administration; the edrophonium (Tensilon) test has therefore been used in the diagnosis of myasthenia gravis.
Steroid induced myopathy
EMG in MG
EMG findings in myasthenia gravis include electrodecremental response and jitter. The presence of a 10% or greater decrement in amplitude of a CMAP between the first and fourth to fifth stimuli with repetitive nerve stimulation suggests an NMJ disorder (see Chapter 9). If there is not an abnormality present on repetitive nerve stimulation but there is a high clinical suspicion for myasthenia gravis and it cannot be confirmed with serologic testing, a single-fiber EMG can be performed. Single-fiber EMG is the most sensitive test of NMJ transmission. Jitter is the variability in the measure of interpotential difference between two muscle fiber action potentials during consecutive discharges of the same motor unit. Increased jitter (or increased interpotential time) is present in patients with NMJ abnormalities, but is not specific for myasthenia gravis. Blocking on single-fiber EMG is failure of a single muscle fiber action potential to appear during the motor unit discharge, and occurs when there is significantly increased jitter.
Categories of congenital muscular dystrophies
There are three major categories of CMDs (1) collagenopathies,(2) merosinopathies, including laminin-α-2-related CMDs, and (3) dystroglycanopathies
Fukuma congenital muscular dystrophy
AR, 2/2 a mutation of the fukutin gene on chromosome 9q.
Clinical: weakness and ocular and CNS abnormalities. Patients are hypotonic and floppy, with joint contractures at the hip, knee, and ankles. The weakness may be generalized, and these patients typically do not learn to walk.
Creatine kinase levels are elevated, and muscle biopsy shows dystrophic changes and reduced α-dystroglycan.
Central nervous system involvement is common, including cognitive developmental delay and seizures. Brain MRI shows abnormalities in gyration and characteristic white matter changes in the frontal regions.
Merosinopathy laminin-α-2 deficiency
Dystrophy
2/2 a mutation in the laminin-α-2 gene, which encodes for the protein merosin, immunohistochemical staining of which is thus reduced in muscles of patients with this disease.
These patients are hypotonic at birth, and have severe weakness of the trunk and limbs. Extraocular and facial muscles are spared. Contractures appear in the feet and hips. Some patients may have seizures.
However, unlike Fukuyama-type CMD, intelligence is generally preserved. MRI shows white matter changes and sometimes cortical abnormalities
Carotid sinus hypersensitivity
Defined by the occurrence of syncope associated with either a period of asystole of at least 3 seconds or a fall of at least 50 mm Hg in systolic blood pressure, or both, in response to pressure on the carotid sinus. In another form of carotid sinus hypersensitivity, hypotension without bradycardia may occur.
Triggers can include a tight collar, turning of the head, or even swallowing, though no identifiable triggers may be present. Symptoms and changes in heart rate and/or blood pressure can be reproduced with carotid sinus massage. Treatment is avoidance of triggers, but when recurrent, pacemaker insertion may be necessary.
The absence of diaphoresis and nausea, and the presence of bradycardia, hypotension, and triggering by neck turning distinguish this from vasovagal syncope.
Carotid sinus innervation
The carotid sinus, located at the bifurcation of the common carotid artery, is innervated by a branch of the glossopharyngeal nerve. The carotid sinus contains specialized mechanoreceptors that are capable of detecting changes in blood pressure (baroreceptors) and heart rate. With stimulation, either mechanically (with applied pressure) or with elevations in blood pressure, mechanoreceptors send signals to the nucleus tractus solitarius in the medulla leading to a reduction in sympathetic tone (leading to a further reduction in blood pressure) and an increase in parasympathetic tone (leading to a reduction in heart rate). Carotid sinus hypersensitivity results from an exaggerated response to baroreceptor stimulation.
McArdle’s disease
(Glycogenosis type V)
Autosomal recessive disorder caused by myophosphorylase deficiency. Myophosphorylase facilitates conversion of glycogen into glucose-6-phosphate; its deficiency will lead to glycogen accumulation/lack of glucose release from glycogen. The typical presentation is exercise- induced weakness and muscle cramps (physiologic contractures: electrically silent when an EMG needle is inserted into the contractured muscles). Unlike normal muscles, when the muscle is exercised there is no production of lactic acid.
On exertion, a sensation of fatigue may ensue; however, if the patient slows down or rests briefly, this sensation may disappear and the patient may be able to continue with the exercise. This is called a “second-wind phenomenon,” which is typically seen in McArdle’s disease, and results from mobilization and use of blood glucose.
Tarui disease
Tarui disease (glycogenosis type VII) is caused by phosphofructokinase (PFK) deficiency in muscle and erythrocytes. This enzyme participates in the conversion of glucose-6-phosphate into glucose-1-phosphate, and therefore, it is similar to McArdle’s disease from the muscular standpoint. In addition, some patients may develop jaundice (due to hemolysis) and gouty arthritis due to PFK deficiency in erythrocytes. Immunohistochemical analysis distinguishes these two disorders.
Cori’s disease
(Glycogenosis type III) is caused by a deficiency in the debranching enzyme, leading to glycogen accumulation. These patients can present with a childhood form with liver disease and weakness or with an adult form characterized by myopathic weakness.
Andersen’s disease
Andersen’s disease (glycogenosis type IV) is caused by a deficiency in the glycogen branching enzyme, and is characterized by hepatomegaly from polysaccharide accumulation, cirrhosis, and liver failure.
Norepinephrine autonomic effects
Acetylcholine autonomic effects
LGMD1
AD
Includes genes from Emery-Dreyfuss
LGMD2
AR
Include genes for Nonaka and Miyoshi
Somatic and autonomic nervous systems
AR distal myopathies
AD distal myopathies
Conus medullaris versus cauda equina symptoms
Conus medullaris: sensory deficits in a saddle distribution, which is usually bilateral and symmetric. Pain is often symmetric, but is not typically radicular. There is usually lower extremity symmetric weakness and sometimes decreased or absent ankle reflexes, but this may be mild. KNEE JERKS PRESERVED. Bowel and bladder dysfunction occur early in the course of the disease, as well as FREQUENT sexual dysfunction.
Cauda equina presents: distinctive radicular pain with an asymmetric distribution. Motor deficits are also asymmetric with evidence of hyporeflexia, LOSS OF KNEE JERKS. Bowel and bladder function may be affected but usually this occurs later in the course and less frequently than with conus lesions. SOMETIMES IMPOTENCE. Spasticity and other upper motor neuron signs will not be present as this is a lower motor neuron disorder.
Vertebral column anatomy
The vertebral column is composed of vertebral bodies, pedicles, and laminae.
- Two pedicles arise from the posterior aspect of each vertebral body, and then fuse posteriorly through two laminae, leaving the spinal canal in the middle within which the spinal cord lies.
- The ligamentum flavum runs in the posterior aspect of the spinal canal, and the denticulate ligament extends on both sides of the spinal cord between the pia mater and the dura mater.
- Between each vertebral body there is an intervertebral disc, which is composed of a central nucleus pulposus and a surrounding annulus fibrosus.
Benedictine sign
Benedictine sign
Claw hand
Froment’s sign
OK sign
Retinitis pigmentosa, neuropathy, ataxia, very low LDL, acanthocytes on peripheral smear
