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NEURO_Myopathy (1).pptx

  1. 1. TUESDAY LECTURE SERIES: MYOPATHY
  2. 2. HISTORY 10 YEARS PTA (+) sudden jerky movements while awake, (-) when asleep (+) frequent episodes of Falls (-) loss of consciousness (-) personality changes INTERIM Jerks became disabling & increased in frequency Can no longer ambulate or feed himself without assistance (+) awkward wide based gait, (+) progressive deterioration in cognition (+) hearing impairment, and proximal muscle weakness 39 yo/male Right-handed from Tondo, Manila CC: progressive myoclonic jerks and weakness J.D.
  3. 3. PAST MEDICAL HISTORY  (-) Hypertension  (-) Diabetes  (-) Renal Disease  (-) Pulmonary tuberculosis  (-) History of trauma
  4. 4. PERSONAL/SOCIAL HISTORY  No data available FAMILY HISTORY  (-) Hypertension/ Cancer/ DM /Stroke /Heart disease /allergies  9th /12 siblings (9 males; 3 females)  4 male siblings – died from an undiagnosed illness (infancy to adulthood)  undocumented crippling illness – older brother; died a year after onset  Mother: 63 yo, married  (+) non-disabling foot drop developed insidiously x 30-35 years;  (+) mild atrophy – R anterior leg muscles  4/5 MMT – UE - proximal muscles  3/5 MMT - R knee flexors & plantar flexors
  5. 5. REVIEW OF SYSTEMS  GENERAL (-) Easy fatigability, (-) Fever, (-) Loss of appetite, (-) Weight loss/gain  HEAD AND NECK (-) Nasal congestion, (-) Otalgia, (-) Otorrhea , (-) Headache  CHEST AND LUNGS (-) Cough, (-) Dyspnea  CARDIAC (-) Chest pain, (-) Edema, (-) Exertional Dyspnea, (-) Palpitations, (-) Orthopnea  DERMATOLOGY (-) Discolorations, (-) Excoriations  ENDOCRINE (-) Heat intolerance, (-) Polyuria, Polydipsia, and Polyphagia  GASTROINTESTINAL (-) Abdominal pain, (-) Nausea, (-) Vomiting, (-) Bleeding  GENITOURINARY (-) Dysuria, (-) Hematuria  MUSCULOSKELETAL (-) Joint malalignments, (-) Muscle pains (-) Limb  PSYCHIATRIC (-) Behavioral changes
  6. 6. PHYSICAL EXAMINATION General Survey Awake, alert, not in cardio-respiratory distress Vital Signs BP: 100/70 (UBP=100-110/70-80) HR: 80 bpm RR: 19 cpm T: 36.8˚ C Skin dry, no active dermatoses HEENT Pink palpebral conjunctivae, anicteric sclerae, no gross head lesions; trachea midline no palpable cervical lymphadenopathies, no distended neck veins; no carotid bruits; Chest/Lung symmetrical chest expansion, clear breath sounds, no rales, no wheezes CVS apex beat 5th ICS LMCL, distinct S1 and S2, normal rate, regular rhythm Abdomen flat, normoactive bowel sounds, soft, no masses/tenderness/previous surgical scars/organomegaly Extremities Grossly normal extremities, Full and equal pulses, no edema, no cyanosis, good capillary refill
  7. 7. NEUROLOGICAL EXAMINATION Mental Status Exam Conscious and oriented patient; Impaired cognition, attention span and immediate memory, no apraxia, no agnosia
  8. 8. Cranial Nerves I No anosmia II No ptosis, pupils: 3mm EBRTL, no visual field cuts, visual acuity: 20/70 OS and 20/200 OD. Fundoscopy: (+) ROR, distinct disc margin, 2:3AV ratio, no hemorrhages, no papilledema, no pigmentary changes II, III Pupils= 3 mm, EBRTL and to accommodation III, IV, VI Bilateral medial and superior rectus palsy V Intact V1,V2,V3; (+) corneal reflex, bilateral VII No facial asymmetry, can raise brow, frown, smile IX,X Uvula midline with intact gag, equal palatal elevation XI Good shoulder shrug XII Tongue base midline
  9. 9. MOTOR EXAM/SENSORY EXAM/DTR  MMT: generalized muscle atrophy, frequent intermittent generalized jerky movements of all extremities lasting for few seconds.  Muscle power was graded 3 & 4 in the proximal & distal muscles of all extremities respectively.  DTRs: Normoreflexive  Sensory: intact vibratory and position senses, negative Romberg’s sign
  10. 10. CEREBELLAR/MENINGEAL/GAIT  Cerebellars: No nystagmus, scanning speech, bilateral dysmetria, dysdiadochokinesia, clumsy heel to knee-shin test  Meningeals: Supple neck, No Brudzinski/Kernig’s signs  Gait: He was unable to stand or walk without support. Marked ataxia with broad based gait and inability to perform tandem walk were observed.
  11. 11. DIAGNOSTICS Total creatine kinase Mildly elevated at 378.3 IU Pure tone Audiometry Moderate bilateral sensory neural hearing loss Interictal EEG Presence of pseudoperiodic delta waves ECG Atrial enlargement and sinus tachycardia EMG/NCV Myopathic changes were seen Cranial CT scan Normal
  12. 12. SALIENT FEATURES 39 | M, no known comorbidities, progressive myoclonic jerks and weakness Ten year history: sudden jerky movements while awake -> became disabling and more frequent -> wide based gait -> progressive deterioration in cognition, hearing impairment, and proximal muscle weakness Family history: 4 males died from an undiagnosed illness (infancy to late adulthood) and mother had non- disabling right foot drop Impaired cognition, attention span, and immediate memory CN II - VA 20/200 OD CN III, IV, and VI - bilateral medial and superior rectus palsy MMT: generalized muscle atrophy, frequent intermittent generalized jerky movements; ⅗ in proximal muscles, ⅘ in distal muscles Gait: Unable to stand or walk without support; Marked ataxia with broad based gait and inability to perform tandem walk No apraxia, no agnosia Other cranial nerves are intact Intact cerebellar: no nystagmus, scanning speech, dysmetria, dysdiadochokinesia, heel to knee shin test Normoreflexive Supple neck, no Babinski/Kernig Intact vibratory and position senses, Negative Romberg
  13. 13. 39 | M, no known comorbidities, progressive myoclonic jerks and weakness Ten year history: sudden jerky movements while awake -> became disabling and more frequent -> wide based gait -> progressive deterioration in cognition, hearing impairment, and proximal muscle weakness Family history: 4 males died from an undiagnosed illness (infancy to late adulthood) and mother had non- disabling right foot drop IS THERE A LESION? Impaired cognition, attention span, and immediate memory No apraxia, no agnosia MMT: generalized muscle atrophy, frequent intermittent generalized jerky movements; ⅗ in proximal muscles, ⅘ in distal muscles Intact vibratory and position senses, Negative Romberg Gait: Unable to stand or walk without support; Marked ataxia with broad based gait and inability to perform tandem walk CN II - VA 20/200 OD CN III, IV, and VI - bilateral medial and superior rectus palsy CN VIII - moderate bilateral sensorineural hearing loss (PTA) Other cranial nerves are intact Cerebellar: scanning speech, dysmetria, dysdiadochokinesia, clumsy heel to knee shin test Normoreflexive Supple neck, no Babinski/Kernig
  14. 14. UMN OR LMN? Impaired cognition, attention span, and immediate memory CN II - VA 20/200 OD CN III, IV, and VI - bilateral medial and superior rectus palsy CN VIII - moderate bilateral sensorineural hearing loss (PTA) Cerebellar: scanning speech, dysmetria, dysdiadochokinesia, clumsy heel to knee shin test MMT: generalized muscle atrophy, frequent intermittent generalized jerky movements; ⅗ in proximal muscles, ⅘ in distal muscles Gait: Unable to stand or walk without support; Marked ataxia with broad based gait and inability to perform tandem walk
  15. 15. WHERE IS THE LESION? Impaired cognition, attention span, and immediate memory
  16. 16. Legally blind on the right eye, deaf bilaterally, eyes are out and down WHERE IS THE LESION? Impaired cognition, attention span, and immediate memory
  17. 17. Legally blind on the right eye, deaf bilaterally, eyes are out and down WHERE IS THE LESION? Impaired cognition, attention span, and immediate memory MMT: generalized muscle atrophy, frequent intermittent generalized jerky movements; ⅗ in proximal muscles, ⅘ in distal muscles
  18. 18. Marked ataxia with broad based gait and inability to perform tandem walk Legally blind on the right eye, deaf bilaterally, eyes are out and down WHERE IS THE LESION? Impaired cognition, attention span, and immediate memory MMT: generalized muscle atrophy, frequent intermittent generalized jerky movements; ⅗ in proximal muscles, ⅘ in distal muscles
  19. 19. TANDEM WALKING AMPLIFYING ATAXIC GAIT
  20. 20. BRAIN, BRAINSTEM, CEREBELLUM, AND MUSCLES
  21. 21. SYNDROME* OF BRAIN, BRAINSTEM, CEREBELLUM, AND MUSCLES
  22. 22. Sudden jerky movements of all extremities observed while awake, lasting for few seconds, disappeared during sleep Jerks were not associated with loss of consciousness or personality changes Resulted in frequent falls and became disabling & more frequent = poor ADLs (ambulate and eating) Frequent intermittent generalized jerky movements WHERE IS THE MYOCLONUS COMING FROM?
  23. 23. WHERE IS THE MYOCLONUS COMING FROM? Sudden jerky movements of all extremities observed while awake, lasting for few seconds, disappeared during sleep Jerks were not associated with loss of consciousness or personality changes Resulted in frequent falls and became disabling & more frequent = poor ADLs (ambulate and eating)
  24. 24. WHERE IS THE MYOCLONUS COMING FROM? Sudden jerky movements of all extremities observed while awake, lasting for few seconds, disappeared during sleep Jerks were not associated with loss of consciousness or personality changes Resulted in frequent falls and became disabling & more frequent = poor ADLs (ambulate and eating)
  25. 25. WHERE IS THE MYOCLONUS COMING FROM? Sudden jerky movements of all extremities observed while awake, lasting for few seconds, disappeared during sleep Jerks were not associated with loss of consciousness or personality changes Resulted in frequent falls and became disabling & more frequent = poor ADLs (ambulate and eating)
  26. 26. WHERE IS THE MYOCLONUS COMING FROM? Sudden jerky movements of all extremities observed while awake, lasting for few seconds, disappeared during sleep Jerks were not associated with loss of consciousness or personality changes Resulted in frequent falls and became disabling & more frequent = poor ADLs (ambulate and eating)
  27. 27. WHERE IS THE MYOCLONUS COMING FROM? Sudden jerky movements of all extremities observed while awake, lasting for few seconds, disappeared during sleep Jerks were not associated with loss of consciousness or personality changes Resulted in frequent falls and became disabling & more frequent = poor ADLs (ambulate and eating)
  28. 28. Cranial CT scan normal WHERE IS THE FRIGGING LESION? Cranial CT scan normal; Abnormal EEG: pseudoperiodic delta waves EMG/NCV - Myopathic changes were seen Total creatine kinase was mildly elevated at 378.3 IU.
  29. 29. LOCALIZE: MYOPATHY PLUS SYNDROME (MAYBE)
  30. 30. DIFFERENTIAL DIAGNOSIS
  31. 31. DIFFERENTIAL DIAGNOSIS Patient’s pertinent data SMA Type IV Mitochondrial Myopathy (MERRF) Limb Girdle Muscular Dystrophy HISTORY: (+) progressive myoclonic jerks - Became disabling and frequent - Frequent episodes of falls (+) progressive weakness **proximal muscle weakness (+) awkward wide based gait (+) progressive deterioration in cognition (+) hearing impairment Mildest form Onset: adulthood Relatively mild proximal limb weakness Myoclonus Seizures Ataxia Muscle weakness Dementia Hearing loss Predominantly proximal weakness Cramps on exercise Lordotic posture Prominent calves progressive wasting (atrophy) may have difficulty standing from a sitting position or walking up stairs difficultly raising their arms over their heads or carrying heavy objects FAMILY HISTORY: - 4 male siblings died from an undiagnosed illness (infancy to adulthood) - Mother: non-disabling right foot drop - can begin in childhood, adolescence or early adulthood after a period of normal development - vary greatly between affected individuals in the same family - affects males and females in equal numbers Slowly progressive: presenting from early childhood to the start of the 3rd decade of life affects males and females in equal numbers
  32. 32. DIFFERENTIAL DIAGNOSIS Patient’s pertinent data SMA Type IV Mitochondrial Myopathy (MERRF) Limb Girdle Muscular PE/NEURO EXAM: Impaired cognition, attention span and immediate memory CN II – VA 20/200 OD CN III, IV and VI – (B) medial and superior rectus palsy generalized muscle atrophy, frequent intermittent generalized jerky movements of all extremities MMT: 3/5 in the proximal muscles & 4/5 in distal muscles scanning speech, bilateral dysmetria, dysdiadochokinesia, clumsy heel to knee-shin test CN: intact MMSE: intact DTR: may be absent or reduced Sensory examination is typically normal tongue fasciculations Cognitive impairment Short stature degeneration of the optic nerve (optic atrophy) altered sensation (pins-and- needles or pain) from nerve damage (peripheral neuropathy) Cardiomyopathy Contractures Cardiac dilatation Heart failure GAIT: unable to stand or walk without support. Marked ataxia with broad based gait inability to perform tandem walk Ataxia, with wide-based gait waddling gait
  33. 33. DIFFERENTIAL DIAGNOSIS Patient’s pertinent data SMA Type IV Mitochondrial Myopathy (MERRF) Limb Girdle Muscular NO MUSCLE BX DONE CK: mildly elevated EMG-NCV: myopathic changes Interictal EEG: abnormal due to presence of pseudoperiodic delta waves ECG: Atrial enlargement and sinus tachycardia gene testing: homozygous deletion of the SMN1 gene EMG: variable features of motor loss consistent with loss of motor neuron function Muscle biopsy: ragged-red fibers CK levels: EMG-NCV: small polyphasic motor units with early recruitment consistent with a myopathic process EEG: generalized spike and wave discharges with background slowing, but focal epileptiform discharges may also be seen Genetic testing: (+) A8344G point mutation Muscle biopsy: muscle fiber degeneration, regeneration, fiber splitting and fibrosis CK levels: elevated EMG: small amplitude polyphasic motor units with early recruitment https://rarediseases.org/rare-diseases/merrf- syndrome/ https://rarediseases.org/rare-diseases/limb-girdle-muscular- Physical Medicine & Rehabilitation, Braddom, 5th edition
  34. 34. IMPRESSION: MITOCHONDRIAL MYOPATHY (MYOCLONIC EPILEPSY WITH RAGGED- RED FIBERS) CANNOT TOTALLY RULE OUT LIMB-GIRDLE MUSCULAR DYSTROPHY
  35. 35. MITOCHONDRIAL MYOPATHY (MYOCLONIC EPILEPSY WITH RAGGED- RED FIBERS) Signs & Symptoms  can begin in childhood, adolescence or early adulthood after a period of normal development.  vary greatly between affected individuals in the same family and between different families  Myoclonus:  distinguishing feature in MERRF  usually the first symptom  Other symptoms: seizures, ataxia, muscle weakness and dementia.  Short stature, degeneration of the optic nerve (optic atrophy), hearing loss, and altered sensation from nerve damage are also common symptoms.  Cardiomyopathy and the heart rhythm abnormality are frequently present. CAUSES:  MERRF syndrome is caused by mutations in mitochondrial DNA (mtDNA).  Mutations are inherited from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass it on to their children.  Heteroplasmy  number of defective mtDNAs may be out-numbered by the number of normal mtDNAs.  The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family.  result in a variety of symptoms in affected family members. Affected Populations: affects males and females in equal numbers. https://rarediseases.org/rare-diseases/merrf- syndrome/ Pfeffer G, Chinnery PF. Diagnosis and treatment of mitochondrial myopathies. Ann Med. 2013;45(1):4-16.
  36. 36. EMG/NCV Myopathic changes were seen Braddom’s Physical Medicine & Rehabilitation 5th Edition
  37. 37. MYOPATHIC LOCALIZATION Electromyography and Neuromuscular Disorders: Clinical Electrophysiologic Correlations 3rd
  38. 38. NERVE CONDUCTION STUDIES  Normal sensory nerve conduction studies  Low Compound motor action potential over muscles with severe atrophy De Lisa’s Physical Medicine and Rehabilitation Principles and Practice 6th Ed (2019) Electromyography and Neuromuscular Disorders: Clinical Electrophysiologic Correlations 3rd
  39. 39. NEEDLE EMG  Abnormal spontaneous activity (positive sharp wave/fibrillation potentials)  Low amplitude, often polyphasic, brief- duration potentials with voluntary contraction  Early recruitment pattern De Lisa’s Physical Medicine and Rehabilitation Principles and Practice 6th Ed (2019) Paganoni, S., & Amato, A. (2013). Electrodiagnostic evaluation of myopathies. Physical medicine and rehabilitation clinics of North America, 24(1),
  40. 40. ROLE OF ELECTRODIAGNOSTIC STUDIES IN THE DIAGNOSIS OF MYOPATHIES 1. Exclude neuromuscular conditions that may mimic a myopathy 2. Provide EMG evidence of the presence of a myopathy (although EMG may be normal in the presence of selected myopathic processes) 3. Characterize the myopathy 4. Identify target muscles for biopsy Paganoni, S., & Amato, A. (2013). Electrodiagnostic evaluation of myopathies. Physical medicine and rehabilitation clinics of North America, 24(1),
  41. 41. SUGGESTED EDX PROTOCOL FOR THE ASSESSMENT OF A SUSPECTED MYOPATHY  1. Routine NCS  At least one motor and one sensory conduction study from one upper extremity and one lower extremity  2. EMG  At least one proximal and one distal muscle from one upper extremity (eg, deltoid, biceps, extensor digitorum communis, or first dorsal interosseous)  At least one proximal and one distal muscle from one lower extremity (eg, iliopsoas, vastus lateralis, tibialis anterior, or gastrocnemius)  Thoracic paraspinals Paganoni, S., & Amato, A. (2013). Electrodiagnostic evaluation of myopathies. Physical medicine and rehabilitation clinics of North America, 24(1),
  42. 42. DIAGNOSTIC TESTING IN MITOCHONDRIAL MYOPATHY I. Testing to confirm the presence of dysfunction in various organ systems II. Tests that definitely address whether the patient is affected by a mitochondrial myopathy Muscle biopsy Molecular genetics Pfeffer, G., & Chinnery, P. F. (2013). Diagnosis and treatment of mitochondrial myopathies. Annals of medicine, 45(1), 4–16.
  43. 43. Pfeffer, G., & Chinnery, P. F. (2013). Diagnosis and treatment of mitochondrial myopathies. Annals of
  44. 44. MUSCLE BIOPSY  Quadriceps femoris or deltoid  In general, the detection of any COX-deficient fibres in individuals <50 years of age, or a higher frequency of COX-deficient fibres at any age (>5%), is strongly suggestive of a mitochondrial disorder.  Electron microscopy: enlarged pleiomorphic mitochondria and paracrystalline inclusions  Respiratory Chain Enzyme analysis Pfeffer, G., & Chinnery, P. F. (2013). Diagnosis and treatment of mitochondrial myopathies. Annals of medicine, 45(1), 4–16.
  45. 45. MOLECULAR GENETICS  mtDNA mutation - mosaic appearance of COX-negative fibres  nDNA mutation - uniformly decreased COX activity  MELAS harbouring m.3243A > G - presence of strongly succinate dehydrogenase-positive blood vessels (SSVs) Pfeffer, G., & Chinnery, P. F. (2013). Diagnosis and treatment of mitochondrial myopathies. Annals of medicine, 45(1), 4–16.
  46. 46. OTHER DIAGNOSTIC TESTS  Skin biopsy – obtain fibroblasts for RCE and DNA for genetic studies  Liver biopsy – to exclude other disorders and is a tissue source for analysis  CoQ10 deficiency in muscle tissue, fibroblasts and white blood cells  Exercise testing with cycle ergometry or treadmill – controversial  Venous pO2 during handgrip testing – excellent specificity, non-invasive screening test for MM Pfeffer, G., & Chinnery, P. F. (2013). Diagnosis and treatment of mitochondrial myopathies. Annals of medicine, 45(1), 4–16.
  47. 47. MEDICAL TREATMENT  There is no specific treatment for MERRF, similar to other mitochondrial disorders.  This condition cannot be cured.  Multiple therapeutic agents are tried to decrease the decrease progression with variable results. DiMauro S, Hirano M. MERRF. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® University of Washington, Seattle; Seattle (WA): Jun 3, 2003
  48. 48.  These therapeutic agents include coenzyme Q10 (CoQ), vitamin B-complex supplementation, and L-carnitine DiMauro S, Hirano M. MERRF. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® University of Washington, Seattle; Seattle (WA): Jun 3, 2003
  49. 49. TOXINS AND PHYSIOLOGIC STRESS  Alcohol and Cigarettes  Inhibit complex IV of OXPHOS  Heat and Cold Stress  exposure to cold can result in severe heat loss and trigger an energy crisis
  50. 50.  Physiotherapy guidance for people with mitochondrial disease http://mitochondrialdisease.nhs.u k/professional-area/care- guidlines/
  51. 51. FATIGUE  Provision of aids and adaptations to conserve energy when walking or performing daily life activities  Exploring individualized exercise interventions to optimize aerobic capacity.  Liaison with Occupational Therapists or Psychologists with experience in assessing and supporting individuals to manage their fatigue.  Sleep studies to explore a person’s sleep.
  52. 52. EXERCISE INTOLERANCE  Respiratory chain dysfunction  Deconditioning  Cardiomyopathy
  53. 53. EXERCISE TIPS/ADVICE:  Keep yourself hydrated and carry water with you when exercising.  Make sure you are well nourished (if diabetic check blood sugar before and after exercise).  Always start off with low intensity and duration.  Spread your training days evenly along the week and have rest days in between, trying to avoid sitting still for too long on rest days.
  54. 54.  A certain level of muscle soreness is to be expected after training (in particular when we are new to a type of exercise). It should not be a concern unless it lasts more than 48hrs.  If soreness lasts for over this time you have probably over done it. Whilst exercising you should feel slightly out of breath, your heart rate should be slightly higher and you should feel slightly warm BUT you should still be able to hold a conversation.  Be aware if there are any changes to the colour of your urine after you have done strenuous exercise. Black or ‘coca cola’-coloured urine can be a sign of muscle damage (myoglobulinuria).
  55. 55.  Complex and Varied  maintain function  prevent contractures, skin break down  reduce risk of aspiration.  maintain function and prevent contractures, skin break down and reduce risk of aspiration.  Orthotics and splinting
  56. 56. REHABILITATION  Aerobic exercises  Endurance exercises  Resistance Jeppesen T.D., Schwartz M., Olsen D.B. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain. 2006;129:3402–3412 “ It is likely the benefits of exercise in Mitochondrial Myopathy are due to reversal of deconditioning, which is a common feature of many muscle diseases. Furthermore- exercise seems to alter the underlying pathology by promoting mitochondrial biogenesis. ”
  57. 57. PROGNOSIS  MERRF is a chronic condition, which is slowly progressive. As explained above, different individuals become symptomatic with different phenotypes and at different ages, even within the same family. Hence, the exact prognosis is difficult to ascertain, but usually, it is poor.
  58. 58. FOLLOW UP  Affected persons with MERRF and their asymptomatic at-risk relatives should have a regular follow-up (e.g., every 6 to 12 months initially) for disease monitoring and the appearance of new symptoms.  It is recommended to have an annual neurologic, ophthalmologic, cardiology, and endocrinologic evaluations to screen for complications
  59. 59. T H A N K Y O U Aral na guys~! End-of-module Exam next week

Hinweis der Redaktion

  • With muscle fiber injury, this enzyme leaks into the serum. Particularly high elevations (50 to 100 times the normal) of CK may be found in acute inflammatory myopathies and early DMD and BMD.
    More slowly progressive dystrophies may have mild to moderate elevations of CK levels
    Normal – congenital myopathies, slowly progressive dystrophies, chronic inflammatory myopathies, myopathies of systemic disease
    Mildly elevated in normal individuals for several days after vigorous exercise

    Pure-tone audiometry is broadly defined as either screening or threshold search. Screening audiometry presents tones across the speech spectrum (500 to 4,000 Hz) at the upper limits of normal hearing (25 to 30 dB for adults, and 15 to 20 dB for children).17 Results are recorded as pass, indicating that the patient's hearing levels are within normal limits, or refer, indicating that hearing loss is possible and a repeat screening test or a threshold search test is recommended.
    Threshold search audiometry determines the softest sound a patient can hear at each frequency 50 percent of the time. This testing requires more time and expertise than screening audiometry.

    Myopathies usually come with cardiac problems



  • The first step in localization in neurology is to determine whether it is an upper motor neuron or a lower motor neuron.
  • Medial rectus = turns the gaze medially

    Superior rectus = turns the gaze upward
  • An impaired stance in the absence of motor weakness or gross involuntary movements is suggestive of cerebellar ataxia or sensory ataxia.

    Sensory ataxia is mainly reflected by gait disturbance, as previously described. In addition, subjects with sensory ataxia will have a positive Romberg sign.

    Stance. A healthy person can stand naturally with feet spread less than 12 cm apart and is able to stand stable with feet together or in tandem for more than 30 seconds.
  • 4 males died from an undiagnosed illness (infancy to late adulthood) and mother had non-disabling right foot drop
  • Present condition started about 10 years prior to admission, as sudden jerky movements of all extremities observed while he was awake, lasting for few seconds, and disappeared during sleep. The jerks were not associated with loss of consciousness or personality changes, however, it resulted in frequent falls

    Myoclonus is a sudden brief (20–250 ms) contraction (positive myoclonus), or a brief and sudden cessation of tonic muscle (negative myoclonus) inducing a simple jerky movement of body part. Myoclonus could have different origins in almost every part of the nervous system, from the cortex to the peripheral nerve, sharing a large panel of etiologies.

    Clonus refers to a series of rhythmic, monophasic (i.e., unidirectional) contractions and relaxations of a group of muscles, differing in this way from tremors, which are always diphasic or bidirectional.

    Myoclonus specifies the very rapid, shock-like contractions of a group of muscles, irregular in rhythm and amplitude, and, with few exceptions, asynchronous and asymmetrical in distribution.
  • Cortical myoclonus is the most common form of myoclonus, seen in both outpatient and inpatient clinical settings. Cortical myoclonus mainly affects the distal upper limbs and face, which reflects the largest cortical representations of these body areas [Caviness, 2009]. It is often focal, but may be multifocal, bilateral or generalized, as a consequence of intracortical and transcallosal spreading of abnormal activity [Brown et al. 1996, 1991a]. It typically occurs on voluntary action and may affect speech and gait. Cortical myoclonic jerks are stimulus sensitive, typically to touch, but sensitivity to visual stimuli is also described [Shibasaki and Neshige, 1987]. Most patients with cortical myoclonus have both positive myoclonus and NM, occurring either independently or together as a complex of the two kinds of myoclonus
  • Epileptic myoclonus (or myoclonic seizure) is defined as the association of myoclonic jerks with an epileptic discharge on EEG (polyspikes or spike/polyspike-wave).
  • Brainstem myoclonus is manifested by generalized jerks and its most striking clinical feature is sensitivity to auditory stimuli. Two main types are (i) startle response, which may be physiologic or pathologic (hyperekplexia), and (ii) reticular reflex myoclonus.

  • Spinal myoclonus may be segmental or propriospinal, reflecting spinal segmental organization and the presence of propriospinal pathways which connect different spinal segments [Brown et al. 1994]. It is generally resistant to supraspinal influences such as sleep (therefore it may persist in sleep) or voluntary action (therefore it is present at rest, independently of activation) and may or may not be stimulus sensitive [Caviness and Brown, 2004].
  • So we’re going to localize it here in the cortex but we’re still not convinced cos we said lower motor neuron
  • Going to be jumping the gun here but…

    Interictal EEG is defined as an electroencephalographic recording that does not contain seizures or ictal manifestations and is therefore obtained in the intervals between clinical attacks
  • **proximal muscle weakness, manifested by: difficulty in getting up from a sitting position and difficulty raising arms above the shoulder level
    SMA
    Spinal muscular atrophy includes a group of genotypically and phenotypically diverse disorders associated with features of LMN loss
    Some forms of SMA are associated with a distal predominant patter of weakness, and therefore have been described with the term distal SMA
    Distal SMA or dHMN have clinical features of: distal weakness and atrophy, reduced to absent reflexes, sensory function, by definition is preserved
    Although a potential manifestation of a MND is a painless foot drop (as manifested by the patient’s mother), the patient shows no other symptoms that are similar to MND or SMA and since the lesion is in the motor neuron
  • SMA
    Spinal muscular atrophy includes a group of genotypically and phenotypically diverse disorders associated with features of LMN loss
    Some forms of SMA are associated with a distal predominant patter of weakness, and therefore have been described with the term distal SMA
    Distal SMA or dHMN have clinical features of: distal weakness and atrophy, reduced to absent reflexes, sensory function, by definition is preserved
    Although a potential manifestation of a MND is a painless foot drop (as manifested by the patient’s mother), the patient shows no other symptoms that are similar to MND or SMA and since the lesion is in the motor neuron – cortical function, cranial nerves should be intact
  • Pseudoperiodic lateralized epileptiform discharges (PLEDs) are EEG abnormalities consisting of repetitive spike or sharp wave discharges that are focal or lateralized over 1 hemisphere, recur at intervals of 0.5-5 seconds, and continue through most of a routine EEG study.
  • General Discussion
    an extremely rare disorder that begins in childhood and affects the nervous system and skeletal muscle as well as other body systems.
    The distinguishing feature in MERRF is myoclonus, consisting of sudden, brief, jerking spasms that can affect the arms and legs or the entire body.
    Signs & Symptoms
    Symptoms of MERRF syndrome can begin in childhood, adolescence or early adulthood after a period of normal development.
    Symptoms and physical findings associated with MERRF syndrome vary greatly between affected individuals in the same family and between different families. Myoclonus is usually the first symptom followed by seizures, ataxia, muscle weakness and dementia. Short stature, degeneration of the optic nerve (optic atrophy), hearing loss, and altered sensation (pins-and-needles or pain) from nerve damage (peripheral neuropathy) are also common symptoms. Cardiomyopathy and the heart rhythm abnormality known as Wolff-Parkinson-White syndrome are frequently present. Occasional symptoms include benign fat cell tumors (lipomas), especially around the neck, and eye abnormalities involving melanin in the retina (pigmentary retinopathy).
    CAUSES:
    MERRF syndrome is caused by mutations in mitochondrial DNA (mtDNA).
    Mutations are inherited from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass it on to their children.
    Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mtDNAs may be out-numbered by the number of normal mtDNAs. Symptoms may not appear in any given generation until the mutation affects a significant proportion of mtDNAs. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.
    Affected Populations: MERRF syndrome is a rare disorder that affects males and females in equal numbers.
    DIAGNOSIS:
    based on clinical findings and molecular genetic testing
    Clinical testing may include measurement of lactate and pyruvate concentrations in blood and CSF.
    CSF protein may also be elevated in MERRF syndrome.
    Electrocardiogram may be used to diagnose heart rhythm abnormalities.
    Muscle biopsy will usually show ragged red fibers. (Abnormal muscle cells are present and appear as ragged red fibers (RRF) when stained with the modified Gomori trichrome and viewed microscopically. MERRF is caused by mutations in mitochondrial DNA (mtDNA))
  • EDX studies, however, are not always needed to diagnose a myopathy. 
  • Electrodiagnostic studies can be extremely important in the evaluation of the patient with myopathy to localize the pathology to the muscle rather than nerve or anterior horn cell. However, electrodiagnostic studies in myopathy may be normal as well, so a myopathic disorder is not ruled out by normal EMG studies.

    Nerve conduction studies should be normal in myopathic disorders
  • Dependent on whether the myopathy is causing active muscle fiber degeneration
    Early recruitment pattern – excessive number of motor units for a given strength of contraction; these findings may be subtle or absent particularly in slowly progressive disorders
    Paraspinal ,suprspinatus, infraspinatus, glutei, iliopsoas
  • > Does not confirm a diagnosis of MM. The tests selected are guided by the pattern of organ involvement in each individual patient.
  • Cytochrome C oxidase

    From a limb muscle

    The major diagnostic feature is the presence of fibres deficient for COX activity, which represents poor activity of complex IV of the respiratory chain

    This testing must be done in fresh or snap-frozen muscle samples, difficult to perform even in specialist laboratories

    RCE Complex I + III deficiency or complex II + III deficiency in CoQ10 deficiency
  • Based on muscle biopsy findings

    MELAS – easily detected in the urine
  •  However, the RCE defect or molecular genetic defect may not be present in fibroblasts in all patients, and as a result this method has lower sensitivity than muscle biopsy

    Controversial – low specificity and sensitivity
  • Patients with MERRF are at increased risk for cardiac arrhythmia and ventricular dysfunction resulting in cardiac failure and sudden death. They are also at high-risk for head trauma due to seizures, respiratory complications, kyphoscoliosis, diabetes mellitus, and thyroid problems
  • Co factros
    possibly enhance enzyme function and result in improved efficiency of energy generation
    serve as antioxidants, which may slow the progression of the disease

    None has demonstrated a striking efficacy in clinical trials, although numerous non-blinded studies and small series have suggested modest efficacy.

    itamins and cofactors are compounds that are required in order for the chemical reactions, which make energy, to run efficiently. By definition, a  cofactor can be made by the body, whereas a vitamin cannot, and therefore must be eaten. For most people, a regular diet contains all the vitamins one could possibly need and their bodies can make as much of any specific cofactor that it needs. For those with mitochondrial disorders, added vitamins and cofactors may be useful.

    Although extremely rare, PMM caused by CoQ10 deficiency will sometimes respond to high dose of CoQ10 supplementation;
  • Alcohol has been know to hasten the progression of some mitochondrial disorders.  Cigarette smoke, probably due to the carbon monoxide, is known to hasten the progression of some conditions.  Remember that carbon monoxide kills by inhibiting complex IV of OXPHOS, why make it worse?  Cigarette smoke will make it worse.

     When going out into the cold, all exposed body parts should be covered, and exposure to extreme cold should be avoided for anything more than a short period. Over bundling can be a problem too

    Patients should avoid direct sunlight on hot days and stay indoors if it is too warm outside. An air-conditioned environment may be needed.
  • s. Whilst only some of these difficulties can be directly addressed physiotherapy input, all should be considered in the development of each individual’s treatment plan.
  • pain is a common and complex complaint (Fig 4). It is important that the severity, irritability and nature of the pain are assessed and understood. Assessment should include possible: triggers for pain, aggravating and easing factors as well as a full biomechanical, postural and functional assessment to understand the potential causes of pain

    Optimising and improving soft tissue length or alignment.  Provision of aids.  Strategies to help pace activity and plan rests in order to manage pain.
  • his can be done by either increasing general levels of habitual physical activity and/or starting a graded exercise program alongside methods of energy conservation.
  • A formal cardiopulmonary exercise test and measurement of lactate at rest and during exercise can help physiotherapists to
    understand the exercise limitations of a patient and be beneficial in guiding exercise prescription

    graded exercise program and/or an increase in day to day physical activity. Progression of exercise by increasing duration and/or intensity of exercise can be challenging and may require prolonged involvement from physiotherapy services.

    It is recommended that each person with mitochondrial disease have his or her cardiac status (blood pressure, ECG +/- echocardiogram, MRI of the heart), serum lactate level, and diabetic status (blood sugar) checked prior to undertaking exercise
  • Ataxia is a term for a group of disorders that affect co-ordination, balance and speech. In this case due to problems with a part of the brain called the cerebellum, Early intervention aimed at maintaining function, preseving mobility and reducing the risk developing secondary complications associated with immobility, are likely to be the most beneficia

    . Dystonia is more prevalent in children with mitochondrial disease and requires close liaison between medical staff, physiotherapists and tertiary neurodisability services to treat effectively

    As with other causes of dystonia that resulting from mitochondrial disease requires a multi-modality approach with medications. Levodopa, Baclofen and Trihexyphenidyl being used alone, in combination or together with targeted botulinum toxin injections
  •  It is likely the benefits of exercise in PMM are due to reversal of deconditioning, which is a common feature of many muscle diseases. Furthermore, in PMM exercise seems to alter the underlying pathology by promoting mitochondrial biogenesis. 
  • Already developed exercise protocols for MM only include classic aerobic leg training on cycle or treadmill. However, most patients need and must do some form of lifting, carrying, or pushing activity in their daily routine. Including arms strength training as part of the patient’s normal exercise program will better prepare them to perform other strength tasks safely and more efficiently

    They fulfilled all the clinical inclusion criteria stated for the study: (1) MM with exercise intolerance or active muscle pain; (2) limited exercise performance, with a degree of impaired VO2max in the maximal exercise testing established as 83% of predicted values, according to equations proposed for normal individuals by Wasserman et al.38; (3) absence of joint or bone deformities; (4) absence of cardiac and respiratory disease assessed by electrocardiogram, cardiac ultrasound scan, chest X-ray, and spirometry tests (FEV1/FVC was required to be 70%); and (5) absence of uncontrolled epilepsy
  • For three nonconsecutive days each week, patients combined cycle exercise at 70% of their peak work rate with three upper-body weight-lifting exercises performed at 50% of maximum capacity. Training increased maximal oxygen uptake (28.5%), work output (15.5%), and minute ventilation (40%), endurance performance (62%), walking distance in shuttle walking test (95 m), and peripheral muscle strength (32%– 62%), and improved Nottingham Health Profile scores (21.47%) and clinical symptoms
  • MERRF is a multisystem disease. It needs a team of specialists for optimal care. Affected persons with MERRF and their asymptomatic at-risk relatives should have a regular follow-up (e.g., every 6-12 months initially) for disease monitoring and the appearance of new symptoms.
    It is recommended to have annual neurologic (epilepsy control), ophthalmologic (for vision changes), cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (for diabetes and thyroid problems). Physiotherapy, occupational therapy, and rehabilitation are important for improving the quality of life and prevent complications

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