Case History. CPC: Recurrent ptosis and visual disturbances. Case History. Case History

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1 CPC: Recurrent ptosis and visual disturbances Recent Advances in Neurology 15 Feb 2013 Presenter: Neel Singhal Discussant: Vanja Douglas Neuropathology: Andrew Bollen Case History 45 year old woman with diagnoses of multiple sclerosis and myasthenia gravis admitted to a local hospital for 2 weeks of progressive weakness, ptosis, and visual disturbances Symptoms preceded by URI Similar symptoms have occurred numerous times in the past Case History Ocular Ptosis Visual scene-skipping, jitter Weakness Fatigue Difficulty with ambulation, stairs, household tasks Systemic Daily worsened migraine Joint pains, abdominal pain, nausea Case History Family notes 2 years of poor memory manifested as misplacing objects, forgetting appointments, and repetitive questioning ROS: Chills, malaise, myalgias, fatigue, palpitations, heartburn, nausea, dysuria, diffuse pain in limbs/back 1

2 Local Hospital Course Started on antibiotics for suspected PNA After neurologic consultation started on 5-day course of IVIG Started on stress-dose steroids given history of prednisone use No clear improvement in symptoms Of note, patient demonstrated single episode of 3 second pause on telemetry Past Medical History Hypothyroidism Diabetes Anemia Multiple Sclerosis: previously on interferon-β1a from Myasthenia Gravis: maintained on steroids intermittently since 2009 Medications on Transfer Levothyroxine 100 mcg PO daily Pyridostigmine 30 mg PO TID Hydrocortisone 100 mg IV q6hrs Pantoprazole 40 mg PO daily Amitriptyline 30 mg PO nightly Doxyclycline 100 mg PO BID Cefazolin 1 g IV q8hrs Colace 200 mg PO BID Family History Father with history of brain tumor Mother with thyroid disease and arthritis 4 healthy siblings 4 healthy children 1 grandson died in neonatal period with multiple systemic complaints 2

3 Social History Lives in Stockton, CA with her husband Physical Exam HR 72 BP 138/75 RR 16 Sat 100% T36.8 Family has moved 4 times in last 10 years due to work obligations Patient has been on disability for the last 3 years No drugs, alcohol, or tobacco Gen: Well-appearing, sitting up in bed Cor: RRR NL S1 S2 Chest: CTA bilaterally Abd: soft, mild tenderness to palpation at LLQ Ext: no edema, intact pulses Skin: No rashes Psych: Occasional lability, irritability. Normal thought content, occasionally tangential. Neurological Exam MS: Alert, oriented. Fluent language. MOCA 22/30. CN: VFFTC, acuity NL, discs without pallor or edema. PERRL. Severe bilateral ophthalmoplegia. L > R ptosis. Facial sensation intact. Mild facial diplegia. Nasal voice without dysarthria. NL tongue strength. Motor: Bulk, tone NL. Neck flexion weakness. No pyramidal weakness. Power testing normal. Reflexes: symmetric 2+ throughout Coord/Gait: FTN/HKS intact. Negative Romberg. Narrowbased gait. Sensory: intact to PP/Vib/LT/prop Basic Laboratories PT 12.5 PTT 14.7 INR 0.9 Tbili 0.7 AST 32 ALT 32 Alk Phos 63 CK 18; B12: 1035; TSH: 1.38 T4 15 RPR negative; HIV negative

4 Obtained prior to transfer 4

5 Additional History Initial onset of visual symptoms Symptom recurrence led to extensive work-up without clear diagnosis Several weeks of worsened ptosis/visual jitter. MRI performed and diagnosed with MS. Started on Avonex. Diagnosed with myasthenia and started on prednisone, pyridostigmine Additional History 2004 Discharge Summary: Laboratories CSF profile noted to be normal -AchR Ab & MuSK Ab negative Imaging Brain MRI: Greater 10 small, scattered white matter T2/FLAIR hyperintensities Spine MRI: Normal VEPs normal CT Chest normal 5

6 Case Discussion Key Questions Are the diagnoses the patient was previously given correct? AKG Images/Erich Lessing Key Questions Is the diagnosis the patient was previously given correct? Is there a critical symptom or sign on which to anchor this case? Robert Fishman The smartest neurologist is always the last neurologist. What additional clues does the history provide or what additional history do we need to obtain? 6

7 Ophthalmoparesis Visual symptoms started 11 years ago Surgery help eye alignment 8 years ago No diplopia Worse when watching moving targets (TV, driving) Fluctuates with episodic ptosis Exam shows ptosis and severe ophthalmoparesis with normal pupils Chronic Progressive External Opthalmoplegia Orbitopathies thyroid eye disease, infiltrative (amyloid, lymphoma), granulomatous (granulomatosis with polyangiitis, sarcoid), idiopathic (orbital pseudotumor) Muscle Kearns-Sayre syndrome, progressive external ophthalmoplegia, oculopharyngeal muscular dystrophy Neuromuscular junction myasthenia Lambert- Eaton syndrome Progressive Ophthalmoparesis Nerve Guillain-Barre/Miller-Fisher Syndrome Cavernous sinus/superior orbital fissure infectios, neoplastic, granulomatous, vascular (C-C fistula) Subarachnoid space bsailar meningitis (infectious, neoplastic, inflammatory) Brainstem unlikely in this case Multiple Sclerosis Intermittent neurologic symptoms Ptosis, weakness, visual symptoms, headache Current exam does not localize to brainstem History of normal spinal fluid, visual evoked potentials, and spine MRI 3 years prior to diagnosis of MS 7

8 NMJ and Myasthenia Gravis? Intermittent ptosis, opthalmoparesis, and weakness triggered by viral infection Exam shows bifacial weakness, lower motor neuron speech, and neck flexion weakness Cognitive decline and lack of diplopia are unusual for myasthenia Normal AchR, MuSK, and EMG/NCS in 2004 Botulism and LEMS: normal reflexes, normal pupils, no autonomic symptoms, slow pace Orbitopathies? Thyroid eye disease Infiltrative processes amyloidosis, lymphoma Granulomatous granulomatosis with polyangiitis, sarcoid Orbital pseudotumor Infectious processes cellulitis, fungal infections Myopathies with PEO Oculopharyngeal muscular dystrophy Oculopharyngodistal myopathy Myotonic dystrophy type 1 Progressive external ophthalmoplegia and Kearns- Sayre Syndrome Other mitochondrial syndromes with PEO POLG, MNGIE, Optic atrophy type 1, TWINKLE Myopathies with PEO AD Oculopharyngeal muscular dystrophy Oculopharyngodistal myopathy Myotonic dystrophy type 1 Progressive external ophthalmoplegia and Kearns- Sayre Syndrome Other mitochondrial syndromes with PEO POLG, MNGIE, Optic atrophy type 1, TWINKLE 8

9 Myopathies with PEO AR Oculopharyngeal muscular dystrophy Oculopharyngodistal myopathy Myotonic dystrophy type 1 Progressive external ophthalmoplegia and Kearns- Sayre Syndrome Other mitochondrial syndromes with PEO POLG, MNGIE, Optic atrophy type 1, TWINKLE PEO & KSS KSS Onset < 20 years, PEO, pigmentary retinopathy, cardiac conduction block, high CSF protein, or cerebellar ataxia Can also have dysphagia, hearing loss, migraine headaches, cognitive decline, endocrinopathies PEO PEO plus limb weakness PEO plus PEO plus other features of KSS Diagnostic Work-up Orbital MRI: T1 Fat Saturated Diagnostic Work-up Orbital MRI: T1 Fat Saturated ON 9

10 Diagnostic Work-up EMG/NCS Normal electrodiagnostic study Motor and sensory nerve conduction studies were within normal limits Repetitive nerve stimulation of the right facial nerve did not demonstrate defect Diagnostic Work-up Advanced Laboratories Ach-R Ab negative Opthalmology consultation Normal exam without retinal degeneration Muscle Biopsy Muscle Biopsy Andrew Bollen MD Professor of Neuropathology 10

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13 Diagnostic Work-up Summary EMG/NCS and serological testing did not support diagnosis of myasthenia MRI suggested significant extraocular muscle atrophy Ophthalmology evaluation was normal without evidence of retinal degeneration Muscle biopsy demonstrated mitochondrial pathology Final Diagnosis? 13

14 CPEO Clinical Features: Onset in 30s Insidious progressive symmetric ophthalmoplegia often without diplopia Bilateral ptosis Failure to respond to pyridostigmine Approximately 50% of patients with systemic features (McFarland et al., 2010) CPEO Associated non-ocular features: Pfeffer et al., 2011 CPEO Significant psychosocial impact (Smits et al., 2011) Fatigue (67.9%) Pain (96.2%) Depression (32.1%) Dependency in daily life (46.4%) CPEO Genetics: Sporadic Most often involve large mtdna mutations POLG mutations Mitochondrial trna associated mutations Multiple dominant and recessive mutations identified Associated with variant syndromes 14

15 Progressive external ophthalmoplegia (PEO)- syndromes Chronic PEO (CPEO) PEO Plus Kearns-Sayre Syndrome (KSS) Progressive external ophthalmoplegia (PEO)- syndromes Taylor & Turnbull (2005) Taylor & Turnbull (2005) PEO Plus Syndromes PEO + Sensory Neuropathy: Earlier onset from Sensory ataxia, dysarthria, mild proximal weakness, and arreflexia Associated with POLG mutations trna-mutation associated PEO Variable age of onset of PEO and ptosis Associate features vary but can include migraine and short stature Kearns-Sayre Syndrome Clinical Features Onset < 20 (later onset extremely rare) PEO, ptosis, pigmentary retinal degeneration Proximal myopathy (90%) Dysphagia (50%) CNS: Ataxia (90%), dementia (85%) Systemic: heart block and endocrine abnormalities Genetics Sporadic large scale mtdna mutations 15

16 CPEO Treatment and Surveillance No clear benefit to CoQ10, creatine, L-carnitine Often recommended given low risk of side effects Moderate exercise may increase ratio of normal mitochondria relative to mutant mitochondria within cells Surgical correction of ptosis controversial Strabismus surgery or botulinum toxin can be useful in select patients Yearly EKG and echocardiograms every 3-5 years Periodic neuropsychological evaluation for cognitive deficits Follow-up Weaned off steroids and pyridostigmine Persistent headache, malaise, and fatigue gradually improved Patient established care with local PMD for diabetes Involved in regular program of exercise Increased family support due to recognition of cognitive decline Summary Suspect PEO in patients with: Onset of ophthalmoparesis and ptosis in 30-40s Negative serological/electrophysiological studies Poor response to typical myasthenia gravis therapies There is wide genotypic overlap and phenotypic variation in PEO, PEO+, and KSS Presence of systemic features may support mitochondrial etiology Acknowledgments Clinical Care Team Dr. S. Andy Josephson Dr. Nancy Oberheim-Bush Dr. Kathryn Crozier Shirin Golkar (UCSF MS3) Dr. Catherine Lomen-Hoerth Dr. Neil Simon 8 South and Long nursing & rehab staff Useful diagnostic testing include: Brain/Orbital MRI, limb muscle biopsy with genetic analysis 16

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18 CPEO Associated non-ocular features: Ataxia Neuropathy Generalized myopathy Cognitive impairment Deafness Endocrinopathy (Hypothyroidism/T2DM) Cardiac conduction defects Diagnostic Work-up MRI: Sagittal FLAIR 18

19 Diagnostic Work-up MRI: Sagittal FLAIR Diagnostic Work-up MRI: Axial T1 Post-gad 19