2The first goal in approaching a patient with a suspected muscle disease is to determine the correct site of the lesion.The second goal is to determine the cause of the myopathy.The third goal is to determine whether a specific treatment is available and if not, to optimally manage the patient’s symptoms to maximize his or her functional abilities and enhance quality of life.
5What is the distribution of weakness? Which negative and/or positive symptoms and signs does the patient demonstrate?Family historyHistoryWhat is the temporal evolution?Are associated systemic symptoms or signs present?Are there precipitating factors that trigger episodic weakness or myotonia?
6Which negative and/or positive symptoms and signs does the patient demonstrate? WeaknessMyalgiaFatigueCrampsExercise intoleranceContracturesMuscle atrophymyotoniamyoglobinuria
7Weakness: Proximal lower extremities: Proximal upper extremities: difficulty climbing stairs, arising from a low chair or toilet, or getting up from a squatted position.Proximal upper extremities:trouble lifting objects over their head and brushing their hair.Distal upper extremities:difficulty opening jars, inability to turn a key in the ignition.Distal lower extremities:tripping due to footdrop.Cranial muscle weakness,dysarthria, dysphagia, or ptosis.
8Fatigue less useful negative symptom Nonspecific abnormal fatigability after exercise can result from certain metabolic and mitochondrial myopathies, and it is important to define the duration and intensity of exercise that provokes the fatigue.
9Myalgia, like fatigue, is another nonspecific symptom episodic (metabolic myopathies)constant (inflammatory muscle disorders)more likely to be due to orthopedic or rheumatological disorders
10Muscle crampThey are typically benign, occurring frequently in normal individuals, and are seldom a feature of a primary myopathyCramps can occur with:dehydration,hyponatremia,azotemia,myxedemadisorders of the nerve or motor neuron (especially amyotrophic lateral sclerosis).
11Muscle contractures uncommon They are typically provoked by exercise in patients with glycolytic enzyme defects.Contractures differ from cramps in that they usually last longer and are electrically silent with needle EMG.EDMD also cause contractures
12Myotonia is the phenomenon of impaired relaxation of muscle after forceful voluntary contraction and most commonly involves the hands and eyelids.Myotonia is due to repetitive depolarization of the muscle membrane.Patients may complain of muscle stiffness or tightness resulting in difficulty releasing their handgrip after a handshake, unscrewing a bottle top, or opening their eyelids if they forcefully shut their eyes.Myotonia classically improves with repeated exercise.
13paramyotonia congenita: ‘‘paradoxical myotonia’’ in that symptoms are typically worsened by exercise or repeated muscle contractions.Exposure to cold results in worsening of both myotonia and paramyotonia.
15Myoglobinuria uncommon manifestation of muscle disease caused by the excessive release of myoglobin from muscle during periods of rapid muscle destruction (rhabdomyolysis).Severe myoglobinuria can result in renal failure due to acute tubular necrosis.If patients complain of exercise-induced weakness and myalgias, they should be asked if their urine has ever turned cola-colored or red during or after these episodes.Recurrent myoglobinuria is usually due to an underlying metabolic myopathyisolated episodes, particularly occurring after unaccustomed strenuous exercise, are frequently idiopathic.
17What is the distribution of weakness? Which negative and/or positive symptoms and signs does the patient demonstrate?Family historyHistoryWhat is the temporal evolution?Are associated systemic symptoms or signs present?Are there precipitating factors that trigger episodic weakness or myotonia?
18What is the temporal evolution? onset,duration, andevolution of the patient’s symptoms
21Myopathies Presenting in Adulthood Muscular dystrophiesThyroidParathyroidLimb-girdleAdrenalFacioscapulohumeralPituitary disordersBeckerToxic myopathiesEmery-DreifussInflammatory myopathiesAlcoholCorticosteroidsPolymyositisLocal injections of narcoticsDermatomyositisColchicineInclusion body myositisChloroquineViral [HIV]StatinsMetabolic myopathiesMyotonic dystrophyAcid maltase deficiencyDistal myopathiesLipid storage diseasesDebrancher deficiencyNemaline myopathy Centronuclear myopathyPhosphorylase b kinase deficiencyMitochondrial myopathiesEndocrine myopathiesIdentifying the age that symptoms began can provide crucial information leading to the correct diagnosis. For example, symptoms of Duchenne mus- cular dystrophy usually are identified byage 3, whereas most facioscapulohum- eral and limb-girdle muscular dystro- phies (LGMDs) begin in adolescence or later. Of the inflammatory myopathies, dermatomyositis occurs in children andadults; polymyositis occurs rarely in children but at any decade in the adult years; and inclusion body myositis oc- curs most commonly in the elderly.
22Evolution and duration episodic periods of weakness with normal strength interictally(periodic paralysis, metabolic myopathies due to certain glycolytic pathway disorders).constant weakness
23Constant weakness acute or subacute progression inflammatory myopathies (dermatomyositis and polymyositis);chronic slow progression over yearsmost muscular dystrophiesIBMnonprogressive weakness with little change over decadescongenital myopathies
24Monophasic or relapsing polymyositis can occasionally have an acute monophasic course with complete resolution of strength within weeks or months.Patients with periodic paralysis or metabolic myopathies can have recurrent attacks of weakness over many years,a patient with acute rhabdomyolysis due to cocaine may have a single episode.
25What is the distribution of weakness? Which negative and/or positive symptoms and signs does the patient demonstrate?Family historyHistoryWhat is the temporal evolution?Are associated systemic symptoms or signs present?Are there precipitating factors that trigger episodic weakness or myotonia?
26Precipitating factors illegal drug or prescription medication use that might produce a myopathy.weakness, pain, and/or myoglobinuria provoked by exercisea glycolytic pathway defect.Episodes of weakness with a fevercarnitine palmityl transferase deficiency.Periodic paralysis is characteristically provoked by exercise or ingestion of a carbohydrate meal followed by a period of rest.Patients with paramyotonia congenita frequently report that cold exposure may precipitate their symptoms of muscle stiffness.
27What is the distribution of weakness? Which negative and/or positive symptoms and signs does the patient demonstrate?Family historyHistoryWhat is the temporal evolution?Are associated systemic symptoms or signs present?Are there precipitating factors that trigger episodic weakness or myotonia?
30Hepatomegalymay be seen in myopathies associated with deficiencies in acid maltase, debranching enzyme,infectious disease.mitochondrial disorder.
31What is the distribution of weakness? Which negative and/or positive symptoms and signs does the patient demonstrate?Family historyHistoryWhat is the temporal evolution?Are associated systemic symptoms or signs present?Are there precipitating factors that trigger episodic weakness or myotonia?
32Family historyA thorough family history is clearly of great importance in making a correct diagnosis.Questions regarding family members’ use of canes or wheelchairs, skeletal deformities, or functional limitations are usually more informative than questions such as, ‘‘Does any member of your family have a muscle disease?’’
33Diagnosis of Myopathy Based on Pattern of Inheritance X-LinkedPeriodic paralysisParamyotonia congenitaDuchenneThomsen diseaseBeckerEmery-DreifussCentral core myopathy"Autosomal RecessiveAutosomal DominantFacioscapulohumeralMetabolic myopathiesLimb-girdleOculopharyngeal muscular dystrophyBecker myotoniaMaternal TransmissionMyotonic dystrophyMitochondrial myopathies
34What is the distribution of weakness? Which negative and/or positive symptoms and signs does the patient demonstrate?Family historyHistoryWhat is the temporal evolution?Are associated systemic symptoms or signs present?Are there precipitating factors that trigger episodic weakness or myotonia?
35What is the distribution of weakness? it is important to know which muscles to test and how to grade their power
36Inspection Atrophy Pseudohypertrophy Fasciculation- MND or neuropathy hypothyroid myopathselective atrophy of the quadriceps and forearm flexor muscles is highly suggestive of inclusion body myositis.PseudohypertrophyDuchenne and Becker dystrophyFasciculation- MND or neuropathyDistal myopathies may have profound atrophy of the anterior or posterior lower extremity compartments.Scapular winingFSHD.(LGMD 2G in 50% of pt)LGMD1B (laminopathy), LGMD2A (calpainopathy), LGMD2C–2F (sarcoglycanopathies).HypertrophyLGMD2C–2F, LGMD2I, (LGMD 2G in 50% of pt)myotonia congenitaamyloidosis,sarcoidosis, andFocal muscle enlargement can also be due to a neo- plastic or inflammatory process, ectopic ossification, tendon rupture, or partial denervation.
38Prominent Neck Extensor Weakness Proximal Limb-Girdle Weakness PATTERN-RECOGNITION APPROACH TO MYOPATHIC DISORDERSPtosis With or Without OphthalmoplegiaDistal WeaknessDistal Arm/ProximalLeg WeaknessProximal Arm/Distal Leg Weakness
40Pattern 1: Proximal Limb-Girdle Weakness The most common pattern of muscle weakness in myopathiessymmetrical weakness affecting predominantly the proximal muscles of the legs and armsThe distal muscles are usually involved, but to a much lesser extent.Neck extensor and flexor muscles are also frequently affected.This pattern of weakness is seen in most hereditary and acquired myopathies and therefore is the least specific in ar- riving at a particular diagnosis
41Pattern 2: Distal Weakness This pattern of weakness predominantly involves the distal muscles of the upper or lower extremities (anterior or posterior compartment muscle groups)The involvement is usually, although not invariably, symmetrical.more commonly a feature of neuropathies
42Myopathies Characterized by Predominantly Distal Weakness Distal MyopathiesOPMDLate adult-onset distalmyopathy type 1 (Welander)Emery-Dreifuss Humeroperoneal Dystrophy*"Late adult-onset distal myopathy type 2 (Markesbery/Udd)Inflammatory MyopathiesInclusion Body MyositisEarly adult-onset distal myopathy type 1 (Nonaka)Metabolic MyopathiesEarly adult-onset distal myopathy type 2 (Miyoshi)Debrancher deficiencyAcid-maltase deficiency*"Early adult-onset distal myopathy type 3 (Laing)Congenital MyopathiesNemaline myopathy*Desmin myopathyCentral core myopathy*Childhood-onset distal myopathy"Centronuclear myopathyMyotonic DystrophyFSHD*"Scapuloperoneal Myopathy*"*" Scapuloperoneal pattern can occur
43Pattern 3: Proximal Arm/Distal Leg Weakness This pattern of weakness affects the periscapular muscles of the proximal arm and the anterior compartment muscles of the distal lower extremity (scapuloperoneal distribution)The scapular muscle weakness is usually characterized by scapular winging.Weakness can be very asymmetrical.
44Myopathies with proximal arm/distal leg involvement (scapuloperoneal) Scapuloperoneal dystrophy,Emery-Dreifuss dystrophy,LGMD1B, LGMD2A, LGMD2C–2F,Congenital myopathies,Nemaline myopathyCentral core myopathyacid maltase deficiency.When this pattern is associated with facial weakness->(FSHD)
45Pattern 4: Distal Arm/ProximalLeg Weakness This pattern is associated with distal arm weakness involving the distal forearm muscles (wrist and finger flexors) and proximal leg weakness involving the knee extensors (quadriceps).The facial muscles are usually spared.Involvement of other muscles is extremely variable.The weakness is often asymmetrical between the two sides, which is uncommon in most myopathies.This pattern is essentially pathognomonic for inclusion body myositis (IBM).This pattern may also represent an uncommon presentation of myotonic dystropy; however, unlike IBM, muscle weakness is usually symmetrical
46Pattern 5: Ptosis With or Without Ophthalmoplegia usually, although not always, occurs without symptoms of diplopia.Facial weakness is not uncommon,extremity weakness is extremely variable, depending on the diagnosis.
47The combination of ptosis, ophthalmoplegia (without diplopia), and dysphagia should suggest the diagnosis of oculopharyngeal dystrophy, especially if the onset is in middle age or later.Ptosis and ophthalmoplegia without prominent pharyngeal involvement is a hallmark of many of the mitochondrial myopathies.Ptosis and facial weakness without ophthalmoplegia is a common feature of myotonic dystrophy.
48Myopathies With Ptosis or Ophthalmoplegia Ptosis Without OphthalmoplegiaPtosis With OphthalmoplegiaMyotonic dystrophyCongenital myopathiesCentronuclear myopathyNemaline myopathyCentral core myopathyDesmin (myofibrillary) myopathyOculopharyngeal muscular dystrophyOculopharyngodistal myopathyChronic progressive external ophthalmoplegia (mitochondrial myopathy)Neuromuscular junction disease (myasthenia gravis, Lambert-Eaton, botulism)
49Pattern 6: Prominent Neck Extensor Weakness ‘‘dropped head syndrome’’Involvement of the neck flexors is variable.Isolated neck extension weakness represents a distinct muscle disorder called isolated neck extensor myopathy.Prominent neck extensor weakness:amyotrophic lateral sclerosis andmyasthenia gravis.
53Creatine KinaseThe CK is elevated in the majority of myopathies but may be normal in slowly progressive myopathies.Duchenne dystrophy, the CK level is invariably at least 10 times (and often up to 100 times) normal.CK may also be markedly elevated:LGMD1C (caveolinopathy),LGMD2A (calpainopathy), andLGMD2B (dysferlinopathy),The CK level may not be elevated incorticosteroid administration,collagen diseases,alcoholismhyperthyroidismprofound muscle wasting
54Differential Diagnosis of Creatine Kinase Elevation MyopathiesMedicationsMuscular dystrophiesHypothyroidism/ HypoparathyroidismCongenital myopathiesSurgeryTrauma (electromyography studies, intramuscular or subcutaneous injections)Metabolic myopathiesInflammatory myopathiesDrug/toxin-inducedStrenuous ExerciseCarrier state (dystrophinopathies)ChannelopathiesIncreased Muscle MassMotor Neuron DiseasesRaceALSSexSMA‘‘Idiopathic HyperCKemia’’Postpolio syndromeNeuropathiesGBSCIDPViral IllnessRace = ck often is above the normal range in some African American individuals and in patients with enlarged muscles.
55Electrophysiological Studies Confirm localizationcan be a guide as to which muscle to biopsy.r/o neuropathy, NMG disease, MND.NCS are typically normal in patients with myopathy.Needle EMG examination: motor unitsBrief duration,small-amplitudeEarly recruitmentNeedle EMG can also provide a clue as to which muscles have had recent or ongoing muscle in- jury and can be a guide as to which muscle to biopsy. It is important to realize, however, that the EMG can be normal in a patient with myopathy, and the results of electrodiagnostic studies need to be evaluated in the context of the patient’s history, neurological ex- amination, and other laboratory studies.
56Muscle biopsySelection of the appropriate muscle to biopsy is critical.Muscles that are severely weak (MRC grade 3 or less) should not be biopsied, since the results are likely to show only evidence of end stage muscle diseasemuscles that have recently been studied by needle EMG should be avoided because of the possibility of artifacts created by needle insertion.
57Biopsies should generally be taken from muscles that demonstrate MRC grade 4 strength. The muscle of choice:biceps.vastus lateralis.The gastrocnemius should be avoided, since its tendon insertion extends throughout the muscle and inadvertent sampling of a myotendinous junction may cause difficulty with interpretation.
58Typical myopathic abnormalities include: central nuclei,both small and large hypertrophic round fibers,split fibers, anddegenerating and regenerating fibers.Chronic myopathies frequently show evidence of increased connective tissue and fat.
59Inflammatory myopathies characterized by:the presence of mononuclear inflammatory cells in the endomysial and perimysial connective tissue between fibers and occasionally around blood vessels ( perivascular)
60Dermatomyositis …….In addition, perifascicular atrophy, characterized by atrophy of fibers located on the periphery of a muscle fascicle, is a common finding.Inflammatory cell invasion of nonnecrotic fibers is not prominent.deposition of the C5b-9 or membrane attack complex on or around small blood vessels
61polymyositis variability in fiber size, scattered necrotic and regenerating fibers,endomysial inflammation with invasion of non-necrotic muscle fibers
62IBMendomysial inflammation with invasion of non-necrotic muscle fiberssmall groups of atrophic fibers,eosinophilic cytoplasmic inclusions, and muscle fibers with one or more rimmed vacuoles lined with granular materialAmyloid deposition is evident on Congo red staining.TDP-43 positiveUbiquitin positiveElectron microscopy demonstrates 15-nm to 21-nm cytoplasmic and intranuclear tubulofilaments
64Mitochondrial disorder The typical muscle histopathology is “ragged red’’ fiberssubsarcolemmal accumulation of abnormal mitochondria stains red.best seen with modified–Gomori trichrome stain
65Type 1 fibers (slow-twitch, fatigue-resistant, oxidative metabolism) stain lightly at alkaline and darkly at acidic pH levels.Type 2 fibers (fast- twitch, fatigue-prone, glycolytic metabolism) stain darkly at alkaline and lightly at acidic pH levels.Normally, a random distribution of the two fiber types occurs, and generally twice as many type 2 as type 1 fibers are identified.
67WIncreased variability in muscle fiber sizedegeneration, regeneration, isolated ‘‘opaque’’ hypertrophic fibers, and significant replacement of muscle by fat and connective tissue.Central nuclei are present in 2% to 4% of the fibers.Type 1 fiber predominance is seen in most patients.Inflammatory cell infiltrates in the perimysium, endomysium, and perivascular spaces and consist mostly of mononuclear cells, especially macrophages.endomysial and perimysial fibrosis with disease progression
68A, C, D, Muscle biopsy of Duchenne muscular dystrophy and (B) normal control. By light microscopy, the biopsy demonstrates marked variability in fiber size,degenerating and regenerating fibers, ‘‘opaque’’ hypertrophic fibers, and replacement of muscle by fat and connective tissue (most findings shown in A and C). Note the lack of these findings in a normal muscle biopsy (B). In C, arrows show small regenerating muscle fibers and a necrotic fiber invaded by mononuclear cells (open arrow). In D, arrows indicatethe dark-staining ‘‘opaque’’ or hypercontracted large fibers. A, B, D, Hematoxylin and eosin; C, modified trichrome.
69Immunostaining of frozen sections of skeletal muscle biopsies Immunostaining of frozen sections of skeletal muscle biopsies. D through N show antidystrophin antibodies using indirect immunofluorescence. A, B, and C display hematoxylin andeosin–stained sections corresponding to D, E, and F respectively. There is complete absence of immunofluorescence at the sarcolemma in a muscle section from a patient with Duchenne muscular dystrophy (DMD) (C and F), compared with the homogeneous staining of the plasma membrane in normal muscle (A and D) and in muscle biopsies from patients with Emery-Dreifuss muscular dystrophy (G), Fukuyama type of congenital muscular dystrophy (H), limb-girdle muscular dystrophy (I), facioscapulohumeral muscular dystrophy (J), myotonic dystrophy (K), and Kugelberg-Welander type of spinal muscular atrophy (L). In a frozen section of muscle from a patient with BMD (B), partial staining of the sarcolemma is observed (E). Note the mosaic pattern of immunostaining in muscle biopsies from a symptomatic (M) and an asymptomatic (N) DMD carrier.
70Nemaline myopathy Type I fiber predominance and atrophy Marked disproportion in fiber size, with uniformly small type I fibers and normal to large type II fibersSarcoplasmic rods (nemaline bodies)Short, granular-appearingSubsarcolemmal and perinuclear localization in type I fibers (especially large rods)Composed of α-actinin, actin, and other Z diskproteins, and appear to arise from, are attached to,and thicken the Z disk (small rods)Intranuclear rods
71Myotubular (centronuclear) Myopathy Is called “centronuclear” because of predominance of small type I fibers with central nucleib.Type I fiber predominance (often small, atrophied)Central pallor noted on ATPase stainingd.Radial distribution of sarcoplasmic strands apparent on NADH reactione.Interstitial connective tissue: normal or mildly increased
72Central Core Disease Type I fiber predominance Central cores Single, well-circumscribed regionsSelectively involve type I fibersDeficient in mitochondria and sarcoplasmic reticulum as well as oxidative enzymes and phosphorylase activity (detected best on sections with oxidative enzyme immunohistochemistry ,as poorly stained central demarcated areas)Extend entire length of muscle fiberIncreased endomysial connective tissue.Often, increased number of internal nuclei
73Myofibrillar myopathy Myofibrillar myopathy. A and B, Trichrome-stained sections show aggregates of dense granular and filamentous amor- phous material and vacuolar change. Immunohistochemistry performed in sections corresponding to that in B demonstrates accumulation of desmin (C) and αB-crystallin (D).
74Molecular Genetic Studies Disorders With Commercially Available Molecular Genetic Studies Performed With Peripheral Blood SamplesDuchenne and Becker muscular dystrophies ”FSHDMD (types 1 and 2) "OPMDLGMD1B, 2A, 2C–2F, and 2I "Congenital muscular dystrophy (FKRP, FCMD, MEB, and POMT1 mutations) "Nonaka myopathy/inclusion body myopathy type 2 "Nemaline myopathy (ACTA1 mutations) "Myotubular myopathy (MTM1 mutations) "MERRFMELAS
76Case 1A 51-year-old man without significant past medicalSlowly progressive muscle weakness for the past 7 years.His symptoms initially began with difficulty walking down stairs because his left knee would ‘‘give out.’’He currently has difficulty arising from a chair and grasping objects with his right hand.
78Current examination reveals intact cranial nerves, sensation, and muscle stretch reflexes. Motor examination in the right upper extremity shows MRC grade 5 shoulder abduction, grade 5 elbow flexion/extension, grade 4 wrist flexion, grade 5 wrist extension, and grade 3 finger flexion.Strength in the left upper extremity is normal except for grade 4+ finger flexion.In the left lower extremity, the patient exhibits grade 4+ hip flexion, grade 3+ knee extension, and grade 4+ ankle dorsiflexion.In the right lower extremity, strength is normal except for grade 4+ knee extension.
79The chronic onset, asymmetrical distribution of weakness, and selective involvement of wrist/finger flexion and knee extensionCK= 500EMG= myopathyMuscle biopsy
81Case 2 Describe and give DDx. Muscle involved: serratus anterior or long thoracic nerveWeakness of trapezius causes winging of scapula when the arm is abducted.Also seen in LGMD
82FSHDnormal deltoidsbiceps, triceps commonly weak, forearm muscles are less involved resulting in a popeye-like appearancewrist flexors stronger than wrist extensorship flexors and quadriceps are weaker, plantar flexors are preserved, ankle dorsiflexion is weak and foot drop may be the presenting symptomScapular winging may be very asymmetric (misdiagnosed as long thoracic nerve of Bell palsy)The genetic abnormality is a deletion in a 3.3-kb repeating sequence termed D4Z4.Chromosome 4