Professor Rounds LSU NEUROLOGY

1. Professor RoundsLSU NEUROLOGY Raisa C. Martínez, PGY-2 29.Nov.12

2. Hospital: Ochsner-Kenner Medical Center • Admission Date: 10/11/12 • Discharge Date: 10/22/12 • Staff Neurologist: Dr. Barton & Dr. Mader • Fellows: Dr. Obih & Dr. Mukardamwala

3. Chief Complaint “My knees are weak.”

4. History of Present Illness 53 yo. Caucasian, R-handed, male with PMHx of SHF, HTN, HPLD, DM2, A-fib, CAD, and COPD who presented to the hospital complaining of progressive weakness in his lower extremities bilaterally. Patient reported the symptoms developed approximately 3 weeks prior to admission, yet according to family members, these symptoms had begun to develop 2 months prior. Weakness developed in both extremities simultaneously and is not ascending in nature. There is also weakness in the upper extremities bilaterally, specifically the shoulders, which began shortly after the leg onset. He endorses that the lower extremity weakness is significantly worse than the upper extremities. Patient cannot climb the stairs of his house, and now is only able to walk with a shuffling gait. Denies any range of motion (ROM) limitations, but does take longer to do activities of daily living (ADL’s).

5. Patient cannot get up from a chair without assistance. • Denies sensory episodes of numbness, tingling, burning or cramping. • Denies pain, tremors, twitching, swelling, redness, or tenderness in muscles or joints. • Denies backaches, arthritis, or musculoskeletal trauma.

6. Review of Systems: (+) • Gen: Unintentional weight loss (15 lbs in 8 wks.), decreased appetite, decreased energy, mild jaundice • CV: lower extremity edema • Pulm: Shortness of breath (chronic problem, yet now requiring O2) • GI: Constipation • Neuro: decreased/abnormal taste • Heme: Easy bruising, R shoulder/back hematoma

7. Review of Systems: (-) • Gen: No fevers, chills or night sweats, no trauma • Eyes: No changes in vision, photophobia or inflammation • ENT: No dysphagia, epistaxis or tinnitus • CV: No palpitations, chest pain, or claudication, or syncope • Pulm: No cough with or without sputum, no paroxysmal nocturnal dyspnea, no orthopnea • Endocrine: no heat/cold intolerance, no increased thirst, no hair loss • GI: No N/V, abdominal pain, distension, changes in stool color or caliber • GU: No dysuria, flank pain, hematuria, changes infrequency, or erectiledysfunction • Neuro: No HA, dizziness, lightheadedness, LOC, AMS • MSK: No arthralgias, no myalgias • Skin: No rash, insect bite or soft tissue infections

8. Conditions: HTN, CAD, SHF (EF 30%), A-fib, DM2, HLPD, COPD, GERD Allergies: NKDA/NKFD Surgeries: CABG (‘95 & ‘96) AICD (2003) Cholecystectomy Family Hx: Mother (75) CAD Father (72) CAD, DM2, HTN No hx. of nerve/muscle disease Social Hx: Smoke: 2pck/d x 35 years, quit 1 month prior EtOH: social events Illicit drugs: none OTC: none Herbs/Remedies: none Lives with mother Recent Hospitalizations: 9/30/12 for Coumadin toxicity and right shoulder hematoma. Coumadin stopped Past Medical History & Chart Check

9. Medications: Spiriva 18 mcg Coreg 25 mg bid Losartan 50 mg ASA 81 mg Plavix 75 mg Nexium 40 mg Amiodarone 100 mg Simvastatin 40 mg Ultram 50 mg PRN Folic acid 800mg Lasix 40 mg …

10. Physical Exam • GENERAL: AAO x3, moderately obese, no apparent distress. • HEENT: atraumatic,+ scleral icterus, no thyromegaly or cervical lymphadenopathy. Supple neck. • CARDIOVASCULAR: Irregularly regular rate and rhythm. No murmurs,rubs, or gallops. • RESPIRATORY: Minimal bibasilar crackles, poor breath sounds. • ABDOMEN: Protuberant, NT/ND,+BS, no hepato-splenomegaly. • EXTREM: + 3 edema bilateral LE, 1+ pulses LE, 2+ UE, Right LE muscle wasting • Skin: + mild jaundice, R shoulder hematoma. No rash, petechiae, or ulcers

11. Orientation Person, Place, Time Memory Remote & recent intact Language No aphasia Fund of Knowledge Appropriate Aware of current events Concentration Appropriate Cranial Nerves: I: Intact (coffee & alcohol swabs) II:25/20 bilateral, VF intact II, III: PERRLA II,IV,VI: EOMI V1-3: intact bilaterally, clenches and grinds teeth, +corneal VII: symmetric facial expression ; abnormal taste VIII: AC>BC, no lateralization IX, X: uvula midline, symmetric palate elevation, + gag XI: TPZ 5/5 ; SCM 5/5 XII:tongue midline Neurologic Exam

12. Motor

13. DTR’s +2 Biceps, Triceps, Brachioradialis bilateral +1 Patellar bilateral 0 Achilles bilateral Babinski: Absent Coordination/Balance No dysmetria, no tremor, no Romberg Gait Wide based, shuffling gait Extra steps to turn around Unable to get up from chair with arms crossed Sensory Decreased pinprick bilateral plantar surfaces Otherwise, intact to light touch, pinprick, vibration, temperature and joint-position throughout …

14. Clinical ApproachDifferential Diagnosis • Onset and Duration: • Hyperacute (24-72 hours) • Acute (< 1 month) • Subacute (1 - 6 months) • Chronic (> 6 months) • Anatomic Classification: • Fiber type: • Motor vs sensory • Somatic vs autonomic • Fiber size • Distribution • Symmetry • Length-dependent • Axonopathy vs myelinopathy (?)

15. Chemistry: 134 105 51 103 Ca = 8.3 4.8 20 1.4 Mg = 2.6 Phos = 3.8 TPr Alb Tbi AST ALT AkP 6.9 2.3 1.3 39 8 82 Hematology: 95.8 11.2 10.8 226 33.5 18.5 Iron = 27 INR = 2.3 Ferritin = 427 PT = 24.7 Folate = 9.8 PTT = 42.7 Vit B12 = 451 HgA1C = 5.4% CRP = 127 ESR = 42 FT4 = 1.14 LDH = 153 TSH = 11.6 Aldo =3.3 Lactic acid = 1.4 CPK = 12 Laboratory Work-Up

16. CSF: Clear, 12 mL total Gluc = 73 Prot = 29 LDH = 16 Wbc = 0 Rbc = 0 Cultures : No organisms Arbovirus Panel : negative Autoimmune: ANA: (-) RF: (-) Thyroperoxidase: (-) Thyroglobulin: 8.3 Infectious RPR : (-) Hep Panel: (-) HIV: (-) …

17. Neuro-imaging Head CT • Remote Left posterior frontal lobe and Right frontal lobe lacunar infarcts Cervical/Thoracic/Lumbar CT • Cervical spondylosis C3-C4 • Mild thoracic and lumbar spondylosis

18. Electrophysiology Sensory Nerve Conduction:

19. Electrophysiology Motor Nerve Conduction:

20. Electrophysiology F-Wave Studies: Needle EMG:

21. Pathology Muscle Biopsy : Right Deltoid • Features of Denervation: • Atrophic angulated fibers • Increased nuclear bags • Increased CD56 • Fiber Type 1 (slow) predominance • No necrosis or infiltration • Normal vasculature • Increased intra-fascicular connective tissue • No RRF, normal stainings (Oil Red O, PAS, SDH, cytochrome, Myophosphorylase, Acid phosphatase)

22. In Summary… 53 yo. male with subacute progressive, symmetric, proximal weakness of arms and legs with associated unsteady gait, and hyporreflexia. Nerve conduction revealed a mixed sensory and motor neuropathy with both axonal degeneration and demyelination.

23. Toxic Neuropathy Amiodarone

24. Amiodarone • Di-iodinated benzofuran derivative initially developed in the 1960s as an anti-anginal agent. • Later used as a cardiac antiarrhythmic agent in the management of supraventricular and ventricular arrhythmias. • Approved for the treatment of refractory and life-threatening ventricular arrhythmias. • Class III antiarrhythmic agent and shares the capacity to prolong the duration of action potentials and refractoriness in Purkinje fibers and ventricular muscle

25. Prevalence of side effects 15% in the first year, 50% long-term therapy An amphiphilic drug that forms intra-lysosomal lipid complexes in multiple tissues: Pulmonary Chronic Insterstitial Pneumonitis, ARDS, Organizing PNA, Amiodarone phosphoplipid complexes in air-spaces, decreased DLCO Thyroid Hyperthyroidism or Hypothyroidism Incidence affected by underlying thyroid status Skin Facial “blue man syndrome” Ocular Corneal microdeposits, optic neuropathy Cardiac Sinus bradycardia, Prolonged QT, potentiates Warfarin Neurologic Adverse Effects

26. Neurotoxicity • Tremor • occurring in 43% and 39% in 2 large series • 6 to 10 Hz action tremor, bilateral and symmetric • clinically indistinguishable from essential tremor • Ataxia • 7% and 37% of cases in these same series • associated with limb ataxia and other findings clearly suggesting cerebellar dysfunction • Optic neuropathy • insidious onset and slow progression of bilateral visual loss • associated with optic disc swelling • Myopathy • without associated neuropathy, with a proximal pattern of weakness and occasional myalgia • Basal ganglia dysfunction • Encephalopathy • Pseudotumor cerebri

27. Neuropathy • Clinical Features : • Symmetric, subacute to chronic, sensorimotor polyneuropathy • Proximal or distal weakness • Large-fiber sensory modalities are typically involved with or without small fiber dysfunction • Occasionally, neuropathy is predominantly motor • Not length-dependent • Evolution may be rapid, mimicking Guillain-Barré • Glove-stocking loss of all sensory modalities, depressed reflexes, and an ataxic gait

28. Electro-diagnostic and Lab Features: • Demyelination and axonal involvement • Reinnervation features • “Myopathic” MUP’s rarely seen • CK levels do not correlate • CSF is normal • Helps distinguish from GBS • Histopathology • Loss of large and small myelinated axons • Muscle is less affected than nerve

29. Pathogenesis: • Direct toxic effect on Schwann cells • Cause of axon loss thoight to be “secondary.” • Half-life (~53 days) predisposes to widespread drug accumulation • Severity and likelihood of developing toxicity uncertain • Age or dose not a risk factors • Length of time receiving medication • Medication metabolism? • Dosing strategy of current era

30. Literature Review Summary: Retrospective medical record analysis of cardiac patients treated with amiodarone at Mayo Clinic between 1998-2006. Neurologic effects that might be attributable to amiodarone were tabulated.

31. Summary: Three patients developed peripheral neuropathy after taking amiodarone for more than 18 months. All had high serum concentrations of amiodarone and its desethyl metabolite; in one patient concentrations in a sural nerve biopsy were 80 times higher than in serum. Peripheral neuropathy is a complication of large doses of amiodarone taken over long periods.

32. Summary: Two patients had slightly asymmetric, mixed, but primarily demyelinating sensorimotor polyneuropathy. One also had a substantial myopathy. The third had an acute neuropathy resembling GBS. Seemingly CK levels did not correlate with clinical or EMG evidence of mypathy. Histologic evaluations of peripheral nerves revealed demyelination, some axon loss and a variable number of characteristic lysosomal inclusions. After discontinuation of amiodarone, two patients improved and one died of cardiac arrhythmia.

33. Main Treatment : • DISCONTINUING Amiodarone • Reversible partially or almost completely in 1-6 months afterwards • May lead to death secondary to cardiac problems

34. Hospital Course • Amiodarone was discontinued by the 3rd day of hospitalization • Neuropathy: • Subjective improved strength and energy • At discharge, able to ambulate 200 feet • Follow up appointment LSU Neurology-Kenner • Pleural effusion with interstitial disease, • PFT: mild restrictive pattern with decreased DLCO • Hypothyroidism • Synthroid 50 mcg • Atrial fibrillation and AICD • Monitor ICD activations

35. References • Alport A, Sander H. Clinical Approach to Peripheral Neuropathy: Anatomic Localization and Diagnostic Testing. Continuum 2012; 18:13-38. • Martinez-Arizala A, Sobol SM, McCarty GE, et al. Amiodarone neuropathy. Neurology 1983;33:643-645. • Pulipaka U, Lacomis D, Omalu B. Amiodarone-Induced Neuromyopathy: Three cases and a review of literature. J Clin Neuromusc Disease 2002;3:97-105. • Fraser Ag, McQueen IN, Watt AH, et al. Peripheral Neuropathy during long-term high dose amiodarone therapy. J Neurol Neursurg Psychiatry 1985; 48:576-578. • Kang HM, Kang YS, Kim SH, Seong JK, Kang DY, Lee HY, Lee BS. Amiodarone induced hepatitis and polyneuropathy. Korean Journal of Internal Medicine 2007;22:225-229. • Charness ME, Morady F, Scheinman MM. Frequent neurologic toxicity associated with amiodarone therapy. Neurology 1984;34:669-671. • Orr C, Ahlskog, E. Frequency, Characteristics, and Risk Factors for Amiodarone Neurotoxicity. Arch Neurol 2009;66:865-869.