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Neurologic Complications of Systemic Disease

Neurologic Complications of Systemic Disease. October 3 rd 2012 Robert Altman MD FRCP(C). Objectives. Highlight “ key points ” in selected topics overlapping between neurology and internal medicine ( Dx and Tx ) Neurologic complications of systemic diseases

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Neurologic Complications of Systemic Disease

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  1. Neurologic Complications of Systemic Disease October 3rd 2012 Robert Altman MD FRCP(C)

  2. Objectives • Highlight “key points” in selected topics overlapping between neurology and internal medicine (Dx and Tx) • Neurologic complications of systemic diseases • Appreciate “common presentations” of the diseases seen in Internal Medicine / Rheumatology clinics or in consultation • Emphasis on multi-media, neuroimaging and clinical reasoningthrough 12 clinical vignettes. • Will not touch upon the “approach to” medicine-related complications in neurologic patients • Should have been covered in PGY1, please refer to www.uptodate.com Nonetheless important and should not ignore...part of RC objectives; managing sick medical patient

  3. “Neurological Borderlands” • Studying the impact of systemic diseases on the nervous system allows for • Consolidatingknowledge of neuroanatomy, medicine, immunology and clinical examination skills. Lateral thinking. • Forming cognitive cross-links and appreciating the complexities in the diagnosis and management of the medically “sick” patient. • Having an organized ‘approach to’ very challenging cases facilitates the diagnostic process • Having a broader appreciation of neuropharmacology and systemic interactions • Understand the lack of evidence based therapies or guidelines in overlap cases because (a) rare entities (b) different specialists often involved in complex patient care; each have different approaches or association guidelines (c) No-one “takes ownership” of these cases • Educating or facilitating transfer of knowledge to colleagues in medicine, psychiatry and neurology

  4. References • Bradley • Continuum x 2 • Royal College notes • Up to Date • NEJM (Images in Clinical Medicine – videos) • Selected review papers: see last slide February 2011 February 2008

  5. Pre-Test • Neurologic manifestations of celiac disease is primarily related to specific vitamin deficiency state(s) T/F • The CNS is the second most common system involved in sarcoid (outside of pulmonary) T/F • Most sensitive biomarker for neurosarcoid is CSF ACE level T/F • Phenytoin is contraindicated in a liver failure patient T/F • Name a purported biomarker that indicates active neuropsychiatric SLE. • SS is one of the classic syndromes associated with sensory neuronopathy T/F • It is safe to use Remicade for RA in a patient with concomitant RRMS T/F

  6. Outline • Neurologic Complications ofHepatic Failure • Hepatic encephalopathy, cirhosis and ALF • Alcohol and the nervous system • Neurogastroenterology • Mini-review of a few ultra-precise topics • Neurologic Complications of Renal Failure • Systemic Inflammatory Diseases • Sarcoid • Sjögren’s Syndrome • RA • SLE

  7. CASE 1 Clinical Scenario 1 • Which of the following is more common in patients with hepatic encephalopathy in the setting of ALF than in patients with HE from cirrhosis? • Asterixis • Bradykinesia • Dysarthria • Seizures • Somnolence

  8. CASE 1 Clinical Scenario 1 • Which of the following is more common in patients with hepatic encephalopathy in the setting of ALF than in patients with HE from cirrhosis? • Asterixis • Bradykinesia • Dysarthria • Seizures • Somnolence

  9. Neurologic Manifestations of Hepatic Failure / ALF

  10. Clinical Clues • Background knowledge of stigmata of chronic liver disease may help when diagnosis is ambiguous

  11. Hepatic Failure • Encephalopathy • Unique • Rigidity *, tremor and hypokinesia (even if asymptomatic in initial stages) • Asterixis in UE’s or LE’s http://www.nejm.org/doi/full/10.1056/NEJMicm0911157

  12. Altered LOC in Liver Patient “Don’t do something, just stand there......” • Ddx • Hypoglycemia • Sodium disturbance • Epileptic • Cerebral edema • Hypoxia (unwitnessed cardiac or pulmonary arrest) • Intoxication or OD • Wernike • ICH (coagulopathic)

  13. Pallidalhyperintensities on T1 Reflects a significant porto-systemic shunt, NOT hepatic encephalopathy Mn deposition (reduced excretion in bile) 90% of patients

  14. Hypoglycemic Coma MRDWI is key sequence NB. Study excluded cardiac / respiratory arrest AJNR Am J Neuroradiology May 2012

  15. CPM: note DWI + and location

  16. Pathophysiology • Porto-systemic shunt with toxins normally filtered by liver gaining direct access to circulation / CNS • Main players • Ammonia • Astrocyte swelling (osmotic mechanisms) • Increased ROS • As no urea synthesis in CNS; glutamine synthesis occurs • Astrocytic swelling • Dysfunction of astrocytic and neuronal function (neurotransmission) • Increased expression of benzodiazepine receptors, augmenting GABAa receptors

  17. Hepatic Failure / Disease • Grade II • Asterixis • Brady • Rigidity • Tremor • Cerebellar dysarthria • Ataxia II

  18. Ammonia • Elevated levels point to “potential hepatic in origin” to change in brain function • Serum levels corroborate broadly with stages of encephalopathy • Substantial overlap exists (stages) • Normal ammonia does NOT rule out HE • So check it. • And trend it. • Include it in a full metabolic panel when investigating any “encephalopathy”

  19. Practical Point Principals of Management of Hepatic Encephalopathy (acute and chronic) • Look for source (occult bleed) • Low protein in diet • Lactulose PO or enema; titrate to 3+ soft BM per day • Antiobiotics • Target urea producing bacteria in gut (Neomycin) • Avoid benzodiazepines (heightened sensitivity); if necessary try Oxazepam. • May need Flumazenil. • ICP management. Propofol, hypertonics. • Consider porto-systemic shunting procedure (TIPPS) • Liver transplant (committee)

  20. CASE 1.5 36 F overdose on acetaminophen Describe the pertinent findings.

  21. Acute Liver Failure (ALF) • Encephalopathy (irritability, insomnia, concentration deficits, disorientation) + • Cerebral edema • Seizures • Generally grades III and IV • ICP monitoring with subdural transducers can be used • Tend to occur with NH4 > 124µmol/L • ICP management • HV, osmotics (watch-out for RF), propofol, targeted natremia (145-155mmol/L) • Seizure control • Controlled trial with prophylactic phenytoin (no survival advantage, but does decrease subclinical seizures and edema) • Appropriate sedation; barbituates, propofol careful use of benzos (midazolam)

  22. Practical Point “Idopathic Recurrent Stupor” (endozepine-4) • Sine qua non is presence of elevated serum (and CSF) endozepine • Physiologically regulated by neurons • Function; Modulate GABA-mediated neurotransmission • Interictally, the patients have normal EEG findings. During the attacks there is diffuse, low-amplitude, unreactive beta rhythm (13–16 Hz). • Administration of intravenous flumazenil, 0.5 to 2 mg or more, reverses the abnormal EEG pattern to normal, reactive alpha rhythm, and correlates with clinical improvement Ref: Metabolic Encephalopathies – Clinics 2011

  23. Brain (1998), 121, 127–133

  24. CASE 2 Quickie – A Neurological Classic • 33M • Anorexia Nervosa • Otherwise no other PmHx • Admitted to psychiatry with severe hypokalemia and bradycardia • Neuro consult; • “please assess” • “r/o organic brain”

  25. CASE 2 Accompanying MR Brain

  26. Practical Point Wernicke’s Encephalopathy • W-A-C-O • Wernike • Ataxia • Confusion / confabulation • Ophthalmoplgia • Clinical Pearls • Appreciate that it occurs outside of ETOH abuse and represents a manifestation of malnourished state • Also that all features need not be present simultaneously • Vitamin deficiency* Which? • Know the treatment for it

  27. Practical Point Wernike’s in Pregnancy • Note Ddx • Molar pregnancy • HyperT4 • Hepatitis • Generally from hyperemesisgraviderum • 6-16 weeks • Tx with thiamine IV until able to handle PO (UTD.com) • 500mg IV TID x 2, then 500mg daily IV/IM QD x 5 • Daily oral administration of 100 mg of thiamine should be continued after the completion of parenteral treatment and after discharge from the hospital until patients are no longer considered at risk. • Magnesium and other vitamins are replaced as well, along with other nutritional deficits if present

  28. Neurologic Manifestations of GI Disease

  29. CASE 3 35F, appendicular ataxia on exam. Gets bloated and has diarrhea when eating rye or wheat. Also noted distal stocking glove polyneuropathy on exam. • Sent to see you from GI for opinion Normal comparison

  30. Gluten Enteropathy (Celiac) • Chronic immune-mediated systemic disease with diverse manifestations including; GI,dermatopathy, neurologic dysfunction • Diagnosis (in predisposed pt’s) • Serum markers + • IgAtTG serology or Anti-EndomysiumAb(IgA EMA) [Anti-gliadinIgG, igA [markers for spectrum of dz] ] • Small intestine bx • Earliest markers are TTG (IgA), anti-gliadin which can be present even before gut involved • It is said tTG implies gut (specific) • Can get neurologic involvement without gut

  31. Gluten Enteropathy (celiac) • Neurologic effects not vitamin deficiency states, rather immune mediated. • IgA + TTG deposits in vessels in brainstem, cerebellum, small bowel mucosa, peripheral nerves, muscles • Cross reactivity with Purkinje cells with atrophy and gliosis • Effects entire neuraxis • Central (brain, cerebellum (gluten ataxia), cord) • Peripheral (‘gluten’ neuropathy, ‘inflammatory’ myopathy) • Treatment • Eliminate gluten (B-R-O-W) completely • ? immunosuppression if despite strict adherence to diet and dropping Ab levels neurologic dysfunction continues to progress • CONTROVERSIAL

  32. Serum from patients with gluten ataxia reacts with Purkinje cell epitopes Perivascularinflammatroy infiltrate PerivascularTg Purkinje loss

  33. Practical Point Name 5 auto-immune or immune mediated diseases (systemic or nervous system) • MG • MS / ADEM • GBS • Dermatomyositis / polymyositis • Devic’s disease (neuromyelitisoptica) • Neuropsychiatric lupus • Rhumatoid arthritis • Sleroderma • Sjogren • Paraneoplastic syndromes +++ (NMDA-R encephalitis, SPS) • Thyroid eye disease (Graves) or Hashimotos’ (SREAT) • Vitiligo • DM1 • Psoriasis • Celiac disease (ataxia, neuropathy) • IBD

  34. CASE 4 Mr. F, 63M stumbles into JGH ER. “confused and ataxic” according to ED. Automatic neuro consult. • CT brain; NIL ACUTE. • ETOH level 120mmol/L, i.e, drunk • 23:30; Unfortunately code white called on bed 12 red A • Psych pt escaped and stabbed the security guard • Mr F has an unwitnessed ‘hallway’ MI out of fear and dies. • Brain autopsy results shown

  35. Describe the most pertinent findings...

  36. Neurologic Manifestations of ETOH Toxicity

  37. ETOH and the nervous system

  38. Practical Point Every Level of the Neuraxis • Acute intox (i.e, drunk) • Alcoholic Dementia • Cerebellar degeneration • “Vermian man” • Wernike-Korsakoff • Polyneuropathy (toxic and malnutrition) • Myopathy • Epileptic (withdrawal or DT’s) • Alcohol – Tobacco Amblyopia • Marchiafava Bignami or CPM (Na shifts) You may very well see all in the same patient...

  39. Because you asked... • Antigliadin antibodies (AGA) • Helpful in assessing compliance to low gluten diet (antibody to breakdown-product of gluten: gliadin), but very poor sensitivity and specificity • IgA AGA a sensitivity of 75–95% and a specificity of 80–90% • IgG AGA a sensitivity of 17–100% (wide variation between studies) and a specificity of 70–80%. • IgA EMA and IgA tTG are based on the target antigen tTG • IgA EMA had a sensitivity of 90–97% and specificity close to 100%; • IgA tTG a sensitivity of 90–98% and specificity between 95–99%;

  40. Neurologic Manifestations of Renal Disease 5-16% incidence of ARF in hospitalized patients Mortality 20-51%

  41. CASE 5 Clinical Example • 52M HTN, DB2, CKD (CRF) • Progressive lethargy, confusion, and tremors • Minimal PO intake x 2-3 days • Found down by wife, with urinary incontinence and rhythmic jerking movements of the extremities

  42. CASE 5 • On exam • 176/100 mm Hg • Bibasilar crackles on lung examination and 2+ pitting edema in the lower extremities • EO briefly to a loud voice but unable to follow complex commands. • Able to state name, and speech dysarthric. • Unable to correctly state the year or the month. • Not at his baseline according to family. • Myoclonus in arms / legs • Bilateral asterixis • Labs: Creat 864 umol/L, K 5.1, Hb 82 • Normal neuroimaging (not shown) What is the next most important test in this patient’s management?

  43. Important to differentiate NCS from Uremic Encephalopathy; very different treatments...

  44. Neurologic Complications • Manifestations of uremic state • Consequence of renal replacement therapy (dialysis) • Combination of the above • CNS, PNS or both • Most complications fail to resolve fully with dialysis or transplantation (and may develop or worsen)

  45. Disease Related • Encephalopathy • Cognitive impairment and Dementia • Cerebrovascular • Movement Disorders • Focal mononeuropathies • Polyneuropathies • Uremic Myopathy • Nephrogenic Systemic Sclerosis

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