17 year old female- respiratory failure, intermittent heart block muscle weakness, & diabetes insipidus

1
17 year old female-respiratory failure,
intermittent heart block muscle weakness,
diabetes insipidus

• Jennifer Frankovich, MD
• Lucile Packard Childrens Hospital
• Stanford University

2
17 year old African American female Initial
Presentation

• Patient collapsed in front of her home.
• Paramedics found her unresponsive and she was
  intubated on the field ? Oakland Childrens
  Hospital.
• Initial arterial blood gas
• pH 7.02
• pO2 181
• pCO2 93
• bicarbonate 45

3
17 year old African American female History of
Present Illness

• Healthy until 3 months prior to her collapse
• morning headaches
• droopy eyes
• appeared sad and smiling less
• moping around the house
• lazy
• Occasionally felt short of breath
• Primary MD diagnosed her with anxiety and
  depression.

4
17 year old African American female History of
Present Illness

• Symptoms gradually progressed
• global fatigue
• knees would buckle
• Intermittent double vision
• Episodes stop breathing approximately 60
  seconds during sleep.
• there was no history of snoring.

5
17 year old African American female

• REVIEW OF SYSTEMS
• Myalgias muscle cramping x 1 year
• PAST MEDICAL HISTORY
• Product of a full term gestation.
• No hospitalizations or prior surgeries.
• Excess intake of liquids as well as a small
  child, frequent polyuria and nocturia.
• Episode of shingles.
• Pilonidal cyst.
• FAMILY HISTORY
• Father has cardiomyopathy of unknown etiology.
• SOCIAL HISTORY
• Patient lives in a suburb of Oakland, with her
  mother and two younger sisters
• No travel abroad or contact with exotic
  animals.

6
17 year old AA femaleMuscle Weakness,
Respiratory Failure, Heartblock, Diabetes
Insipidus Physical Exam

• Intermittent ptosis and lateral rectus palsy
• Facial muscle weakness
• Hypophonic speech with a nasal quality
• Proximal Muscle Weakness 3-4/ 5
• Draining pilonidal cyst buttocks

7
17 year old African American female In the
Intensive Care UnitWhat happened?

• No evidence of intrinsic lung disease.
• Intubated for 5 days
• failed extubation several times
• was extubated to BIPAP.
• 24-hour BIPAP assistance for 6 weeks.

8
In the Intensive Care Unit Heart Block

• Hospital Day 2-4
• Intermittent Bradycardia
• Episodes of 3rd degree heart block, 4 second
  pauses
• Persistent 1st degree AV block
• Occasional Wenckebach episodes
• Hospital Day 6
• Persistent 1st degree heart block
• No further 3rd degree block
• Echocardiogram indicted normal cardiac structure
  and function.

9
In the Intensive Care UnitHypernatremia

• Initial blood chemistries revealed hypernatremia
  (Na 150-155)
• ?DDAVP was given with little response
• ?Nephrogenic Diabetes Insipidus

10
In the Intensive Care UnitNeurologic Evaluation

• Head CT scan- normal
• Cerebral Spinal Fluid Studies- normal
• EEG- normal
• Brain MRI
• absent posterior pituitary granules
• central diabetes insipidus?

11
Sleep Evaluations

• Polysomnogram was obtained after extebation
• Apneas of 40 seconds with severe desaturations
  and hypercapnia.
• Initial diagnosis central hypoventilation
• Repeat polysomnogram (Hosp Day 21)
• Continued hypoventilation and apneas lasting 30
  to 35 seconds with desaturations as low as 54.
• She did not respond to these episodes of hypoxia
  with spontaneous increase in respiratory rate or
  total volume, though she did have episodes of
  gasping.

12
Neuromuscular Disease Evaluation

• Edrophonium test (Hospital Day 15)
• ? Minimal improvement of ptosis eye movements.
  
• Neostigmine challenge (Hospital Day 25)
• Minimal transient improvement in
• cranial nerve upper extremity strength
• ? No improvement in lower extremity strength.
• Repetitive nerve stimulation
• ? Irritability of the muscles
• ? Inducible fatigue NOT present
• Acetylcholine receptor antibody
• ? Negative

13
Neuromuscular Disease Evaluation

• Neurologists concluded that she did not have
  myasthenia gravis
• Minimal response to acetyl cholinesterase
  inhibitors
• No inducible fatigue during the electrodiagnostic
  testing
• Negative serologic test for the Acetylcholine
  Receptor anitbody

14
Neuromuscular Disease Evaluation

• Muscle biopsy (Hospital Day 31)
• Nonspecific mild changes in muscle fibers
• Few subsarcolemma crescents with few
  hypertrophied mitochondria.
• There was no evidence of muscle fiber
  hyperplasia.

15
Hospital Course

• Continued to suffer from proximal muscle weakness
• upper extremity strength ranking 3 to 4 out of 5.
  
• difficulty with walking standing.
• Ptosis and diplopia became so severe that she
  required patching of one eye to relieve diplopia.
  
• Edrophonium test was repeated on Hospital Day
  35
• minimal improvement of ptosis
• IVIG was given Hosp Day 35-39
• No improvement

16
Hospital Course

• Ophthalmologic examination revealed papilledema
  and retinal hemorrhages leading to the
  consideration for pseudotumor cerebri.
• No evidence of retinitis pigmentosum

17
Hospital Course

• Pyridostigmine (Hospital Day 35)
• 60 mg q 4 hours for 1 week
• Good days sit up walk
• Bad days unable to get out of bed
• ? Did not follow the pattern of progressive
  improvement that would be expected if her primary
  process was myasthenia gravis.

18
Hospital Course

• Leukopenia during first month of admission
• Nadir white blood cell count 2.6, ANC 1300
• 2nd hypoxic injury vs ranitidine
• Ranitidine was discontinued ? spontaneous
  resolution
• 2 months later? lymphopenia
• Hemoglobin was mildly depressed with low MCV
• Iron supplementation
• Coagulation studies and platelet studies were
  normal throughout the admission.

19
Hospital Course

• Negative blood cultures, CSF cultures and urine
  cultures.
• Tuberculosis ruled out
• Pilonidal cyst
• Wound culture indicated coagulase negative
  Staphylococcus and heavy diphtheroids.

20
Muscle Weakness Responds to Corticosteroids

• Trial of Corticosteroids (Hospital Day 54)
• 1 gram Methylprednisolone IV x 3 days
• Some improvement of proximal muscle strength
• Improved FVC FROM 35 TO 77
• Decreased settings on overnight BIPAP
• Improved ptosis diplopia
• Converted to 60 mg daily of oral prednisone
• Discharged home ? f/u outpatient clinic

21
17 year old Myopathy, Now inOutpatient
Rheumatology Clinic

• Neuromuscular Disease?
• Metabolic Myopathy?
• Channelopathy?
• genetic, autoimmune, paraneoplastic
• Lymes disease?
• Atypical presentation of a rheumatic disease?

22
17 year old with myopathyDifferential Diagnosis

• Metabolic Myopathy
• Lipid
• Carnitine deficiency syndromes
• Fatty acid transport defects
• Defects of ß-oxidation enzymes
• Glycogen and glucose metabolism
• Myoadenylate deaminase deficiency
• Mitochondrial energy production defects

23
17 year old with myopathyDifferential Diagnosis

• Mitochondrial Defect?
• Chronic progressive external ophthalmoplegia
• mitochondrial disorder with large deletions of
  mitochondrial DNA
• Kearns-Sayre syndrome
• heart block
• weakness of facial, pharyngeal, trunk and
  extremity muscle
• retinitis pigmentosa, deafness, short stature

24
17 year old with myopathyDifferential Diagnosis

• Oncology Evaluation
• Repeat MRI of the pituitary gland and stalk
• continued absence of posterior pituitary granules
• Concerning for lymphocytic histiocytosis or
  germinoma
• Skull x-rays negative
• Beta-HCG and Alpha Fetal Protein negative
• Evaluation for occult malignancy ? paraneoplastic
  process
• CT neck, abdomen, pelvis- negative
• MRI Right Femur (evaluation 2nd pain)? lesion
• PET scan- negative

25
17 year old with myopathyDifferential Diagnosis

• Paraneoplastic syndrome?
• Primary autoimmune Channelopathy?
• Calcium channel antibodies
• Striational antibodies
• Purkinje cell antibodies
• Mild evidence of neuromuscular hyperactivity
  GAD65, CRMP-5
• AchR Ab (both binding and modulating Abs)
• SSA, SSB (?x-react with calcium channels)

26
17 year old muscle weakness Rheumatology
Evaluation

• Sarcoidosis evaluation negative
• Angiotensin Converting Enzyme, Lysozyme, serum
  calcium, chest x-ray, chest CT normal
• Behcets
• Vasculitis evaluation negative
• Antineutrophil antibody SLE work-up negative.
• Autoimmune mediated myositis
• CPK and aldolase normal.

27
17 year old with myopathyDifferential Diagnosis

• Repeat Myasthenia Gravis Work-up
• AchR Ab (binding, blocking, and modulating)
• Anti-MUSK antibodies
• Repeat EMG with single fiber studies

28
Myasthenia Gravis (MG)

• Antibodies
• post-synaptic components of the neuromuscular
  junction (NMJ)
• lead to impaired neuromuscular (NM) transmission
• skeletal muscle weakness.
• Most common disorder of NM transmission.
• prevalence in the US 14 per 100,000 people
• Subtypes
• widespread weakness (most common)
• purely ocular muscle weakness (10 of cases)

29
Myasthenia Gravis (MG)

• Classic MG-
• antibodies to the acetylcholine receptor (AChR)
• found in up to 80 of patients with MG
• Seronegative MG
• refers to the 20 of patients with myasthenia who
  have a negative assay for AChR-Ab
• Still thought to be an antibody-mediated disorder
• serum passively transfers a neuromuscular defect
  to mice
• plasma exchange improves weakness
• babies born to these mothers? transient neonatal
  myasthenia.

30
Myasthenia Gravis (MG)

• Muscle specific tyrosine kinase (MuSK)
• Surface membrane enzyme
• Aggregate AChR of the developing NMJ
• Its role in mature muscle is not yet clear.

31
Myasthenia Gravis (MG)

• MuSK antibodies
• present in 40 -50 of patients with generalized
  seronegative MG.
• have not been found in patients with purely
  ocular myasthenia
• have not been found in conjunction with anti-AChR
  antibodies.

32
MuSK- Positive Myasthenia Gravis

• Clinical Features
• Onset at any age
• Female preponderance
• Oculobulbar form
• diplopia, ptosis, and dysarthria
• not purely ocular MG
• Restricted "myopathic" form
• prominent respiratory and/or proximal weakness
• especially neck extension
• Weakness predominantly neck, shoulder, muscle.
• Oropharyngeal muscles, severely atrophied in
  some
• Unpublished observations- J. Newsom-Davis, M.E.
  Farrugia, P. Anslow, R. Kennett, A. Vincent

33
MuSK- Positive Myasthenia Gravis

• Electrodiagnostic testing - atypical for MG
• Repetitive nerve stimulation studies are
  frequently normal in limb muscles
• Single Fiber Electromyography may be abnormal
  only in muscles that are severely involved.
• Muscle biopsy does not show myopathic features

34
MuSK- Positive Myasthenia Gravis

• Cholinesterase inhibitors
• produce a variable response in MMG
• exacerbate weakness
• Thymectomy- does not appear to benefit these
  patients
• Plasma exchange- good response
• Immunotherapy- early, aggressive