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NP
NephrologyKatie Connolly, Melanie Ostrekher and EliAa Rennert-May, chapter editors Doreen Ezeife and Nigel Tan, associate editors Steven Wong, EBM editor Dr. Ramesh Prasad, Dr. Martin Sc:hreiber and Dr. Gemini Tanna, staff editorsBasic Anatomy Review ................... 2 Anatomy of the Kidney Renal Structure and Function Renal Hemodynamics Differential Diagnoses of Common Presentations . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Azotemia Proteinuria Hematuria Assessment of Renal Function ............. 6 Measurement of Renal Function Urinalysis Urine Microscopy Urine Electrolytes Electrolyte Disorders. . . . . . . . . . . . . . . . . . . . . 9 Sodium Homeostasis Hyponatremia Hypernatremia Potassium Homeostasis Hypokalemia Hyperkalemia Acid-Base Disorders .................... 16 Metabolic Acidosis Metabolic Alkalosis Renal Failure .......................... 19 Presentation of Renal Failure Acute Kidney Injury (AKI) ................ 20 Approach to AKI Chronic Kidney Disease (CKD) . 21 Management of Chronic Kidney Disease Renal Replacement Therapy ............. 22 Dialysis Renal Transplantation Glomerular Disease .................... 23 Terminology of Glomerular Changes Presentation of Glomerular Disease Investigations for Glomerular Disease Secondary Causes of Glomerular Disease Infections and Glomerular Disease Tubulointerstitial Disease ............... 27 Tubulointerstitial Nephritis (TIN) Acute Tubular Necrosis (ATN) Analgesic Nephropathies Vascular Diseases of the Kidney .......... 30 Large Vessel Disease Small Vessel Disease Systemic Diseases and the Kidney ........ 32 Hypertension (HTN) Hypertensive Nephrosclerosis Renovascular Hypertension Renal Parenchymal Hypertension Multiple Myeloma Malignancy Diabetes and the Kidney ................ 34 Cystic Diseases of the Kidney ............ 36 Adult Polycystic Kidney Disease Medullary Sponge Kidney Autosomal Recessive Polycystic Kidney Disease Common Medications .. 38 Landmark Nephrology Trials .. 39 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Toronto Notes 2011
Nephrology NPI
NPl Nephrology
1'oroDio
2011
Basic Anatomy ReviewAnatomy of the Kidney
Renal Structure and FunctionThe Nephron basic structural and functional unit ofthe kidney, approximately I million per kidney 2 main components: glomerulus and attached renal tubule (Figure I) direction of blood flow: afferent arteriole -+ glomerular capillaries -+ efferent artuiale -+ vasa recta (the capil.laries surrounding the tubules) -+renal venules
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1. N1p1Jnm Compa1antsTlble 1. MaJor Fu1dons of the Kidneys1. Willa EKrltiGn
Ghmarular fi1nl1ionTubailr secretion Tub.-r calllxllism Tubailr tllaCI and Wllllr rubsGiptilll Tubaar Kseaetion Tub.-r HaecratiCII HCO, synlheais ..:1 rBaa!ption Tubular Ca, Mg. P04 lnllspartElytlqail!lil pracb:lian lcorttxl Vitamin Ddvation [25[0H)D 1,25(0HJDI Ranil praductian (JG applfiiUi)
(urea, Cl)
Eiu:mian of nitragnJUs prDib:ls of pratailrnelllbalism
Excretion af organic (!Ne) and Dfllllnic bases (Cr) llnllkdawn end ucratian af drugs {..tDalicl, diul'llicll) end peplida hlmlanes (mast pituillry harmCIIIIS, ilsUin.Clllllds vduma s1a1us and osmolar balance Clllllds pllillssium cai!CI!nlnllian Al:id-basa balance Al:id-basa balance .Min Ca. Ma-1'04 harnaastasis Calcium hiDII!IISialis
Red lilad eel proU;Iian
Allin VIICUI.-ra&i&Wlcellllaldastlmle sacratian Allin ECF Allin VIICUiar rnista1ceGlucose !llp!iY lllllintailed in prnlanged staiYIIIion
....aod ............... Na IIKL18tian Ranil praductianGluconeogereis tfmm lacbde, py!\MII8 end smila acids)
'IbroDlo Nota 2011
Buic Anatomy Review
Nephrology NP3
The Glomerulus site where blood constituents are filtered through to the kidney tubules fur excretion or reabsorption consistB of following cell types 1. capillary endotbelial cells and podocytes support the glomerular basement membrane (GBM) and furm the plasma filtration apparatus 2.mesangialcells have contractile properties and produce YllSoad:i.ve substances to help control blood flow 3. parietal epithelium covers the interior of Bowman's capsule filtration occurs aaoss the GBM Into Bowman's space (Figure 2) filtration barrier: conaists ofcapillary endothelium, GBM. podocyte filtration alit& particles are selectively filtered by size (20 mmolJL) in the setting of acute renal failure: indicates renal disease vs. pre-renal high urine Na (>40 mmolJL) in the setting of hyponatremia: generally from causes such as diuretics, tubular disease (e.g. Bartter's syndrome), SIADH additionally, urine pH is useful to grossly assess renal acidification "low" pH ( 100 cc,lhr, < 1DD mOsmiL) in lha sstting of hyponalr8mia is u.uaUy thefi!$1: sign of dangerously rapid C01111Ction of serum &Odium
... ' .-----------------. ,Conection of Na in hyponab8mia should dlfinitlly known to t. 5.0 mEq!LApproach to Hyperkalemia 1. emergency measures: obtain ECG, if life threatening begin treatment inunediately 2. rule out factitious hyperkalemia; repeat blood test 3. hold exogenous K, and any K retaining medications 4. assess potential causes of transcellular shift 5. estimate GFR (calculate CrCl using Cockcroft-Gault) 6. if normal GFR, calculate TTKG = (Uk/PJ4 weeks
Treatment1. preliminary measures pre-renal correct prerenal factors: optimize volume status and cardiac performance, hold ACEI/ARB renal exclude reversible renal causes: die nephrotoxic drugs, treat infection, and optimize electrolytes post-renal consider obstruction: structural (stones, strictures) vs. functional (neuropathy) treat with Foley catheter, indwelling bladder catheter, nephrostomy, stenting 2. treat complications fluid overload NaCl restriction high dose loop diuretics hyperkalemia (refer to Treatment of Hyperkalemia, NP16) adjust dosages of medications cleared by kidney 3. definitive therapy depends on etiology note: renal transplant is not a therapy for AKI
Toronto Notes 2011
.Acute Kidney Injury/Chronic Kidney Disease (CKD)
Nephrology NP21
Prognosis high morbidity and mortality in patients with sustained AKI and multi-organ failure
Chronic Kidney Disease (CKD)Definition abnormal markers (Cr, urea) GFR 3 months or kidney pathology seen on biopsy or decreased renal size on U/S (kidneys 50%) focal: some glomeruli affected terms applying to an indMdual glomerulus global: entire glomerulus abnormal segmental: only part of the glomerulus abnormal Types of Changes proliferation: hyperplasia of one ofthe glomerular cell types (mesangial. endothelial, parietal epithelial), with or without inflammatory cell infiltration membranous changes: capillary wall thickening due to immune deposits or alterations in basement membrane crescent formation: parietal epithelial cell proliferation and mononuclear cell infiltration from crescent-shape in Bowman's space
bltdll: No sigricanl dillerence il uvivll hmrd NHD 11111 DlX. Significlri survinl blllefitlor pllierQ _.dergoing LlX venus NHD. Signliclnt rnonalty hmnllllia l'llll:tian willlllX 10.511MilllllllfliRe in hllll1l ratialor D1X Vlnlll NHD ralnlce. Cancbin: lflllu mlllty1D DlX.lit is iriaricr1D llX.
wu
CIUII mlllbllty
Presentation of Glomerular DiseaseImportant Points To Remember each glomerulopathy presents as one of 4 major glomerular syndromes acute nephritic nephrotic rapidly progressive glomerulonephritis asymptomatic urinary abnormalities each glomerulopathy can be caused by a primary disease OR can occur secondary to a systemic disease some glomerulopathy can present as more than one syndrome at different times1. ACUTE NEPHRITIC SYNDROME
Clinical/Lab Features proteinuria (but 3.5 g/1.73m2/d) hypoalbuminemia edema hyperlipidemia (elevated LDL cholesterol),lipiduria (fatty casts and oval fat bodies on microscopy) hypercoagulable state (due to antithrombin III, Protein C and ProteinS urinary losses) patient may report frothy urine glomerular pathology on renal biopsy: minimal change disease (or minimal lesion disease or nil disease) - i.e. glomeruli appear normal on light microscopy membranous glomerulopathy focal segmental glomerulosclerosis (FSGS) membranoproliferative glomerulonephritis nodular glomerulosclerosis each can be idiopathic or secondary to a systemic disease or drug (sirolimus can cause proteinuria without obvious glomerular pathology) Tabla 11. Naphrotic Syndroma Minimal
Prwentation -' Nepllratie Syndnlme 1. Sevn proteinuria (>3.5 Qfdl 2. Hypollbumilemia 3. Edama 4. Hyperlipidemia, lipiduria 5. Oval fat bodies (microscopy( 6. Hypereoag!Jahle stile (antithrombin Ill, protein Cand pnrtein S lost in urineI
Change
Membranous Glomeruloplllly HBV, SLE, solid breast. Gil
Focal S..-nlll Mambranoprolifaratiwe Glomeeulosderosis Glomeeulonephrilil
Nodular Diabetes mellitus, amyloidosis
Secondary CIUSIS DI\IIICIIUIISTh. .py
Hodgkin's lymphomaNSAIDs
Reflux ne(h'opathy, HIV; HBV, obe&ity
HCV, malaria. SLE, leukemia, lymphoma, inlecl8d &hunt
Gold, penicillamine Heroin Recllce BP, ACB, &teroids Steroids, ACEVARB fur proiBinuria Aspirin, ACEI, dipyridamole Treat undBriying controversial cause
Steroids
The Nephritic-Nephrotic Spectrum glomerular pathology can present with a clinical picture anywhere on a spectrum with pure nephritic and pure nephrotic syndromes at the extremes (see Figure 15)Naphratic lntarmadiate
NaphriticHamatu.ria, "-
[ ProtainaraFSGS Membranous gtomarulopathyMinimal change Membranoproliferative GN Focal proliferative GN lgA nephropllhy ldioplllhic membranoprolifenrtive GN
Diffuse prolifen.tive GN Crescentic GN
HBV, HCV SL.E Cryoglobulinamia
Figura 15. Tha Spectrum of Glomerular Pathology
Toronto Notes 2011
Glomerular Disease
Nephrology NP25
3. RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)Clinical/Lab Features a subset of nephritic syndrome in which renal failure progresses in weeks to months crescent formation usually seen on renal biopsy RBC casts and/or dysmorphic RBCs in urine classified by immunofluorescence staining (see Table 12) treatment: underlying cause for postinfectious; corticosteroids + cyclophosphamide or other cytotoxic agent + plasmapheresis in select cases prognosis: 50% recovery with early treatment, depends on underlying causeTabla 12. RPGN Classification
RPGNTpl: AJrti.GBM m iltld .. %111RPGNC. 15% of cases lmmuno.ftuorncence Linear pattern due to lgG 111d SUing Pattem C3 deposition along capillary loopsAntibodies against type IV collagen in GBMPrimuyc....
RPGN Type II: Immune Complex miltlll24% of cases Granular pattern due to subendlllhelial or subepithelial deposits DllgG and C3 Most often di&sa&e
RPGN Type Ill: Non-immUDI lllldillld (i.e. piuci-immune)60'J(, of cases
No immune stailingVasculitis of glomerular capillaries Idiopathic Wegener's {c-ANCA +vel Microscopic polyangiitis (p-ANCA +vel Cilurv-Stn!uss (ANCA -vel
z to systemic
Idiopathic anti.{lBM disease Goodpasture's disease
lgA nephropathy Post-infectious GN, SLE, Cryoglobulinemia, Henoch-Sclxlnleil pLrpura
s-nduvc....
4. ASYMPTOMATIC URINARY ABNORMALITIESClinical/Lab Features isolated proteinuria (usually 50 years old smoking other atherosclerotic disease severe/refractory HTN and/or hypertensive crises asymmetrical renal size increasing Cr with ACEUARB flash pulmonary edema with normal LV function must establish presence of renal vessel stenosis and prove it is responsible for renal dysfunction duplex Doppler U/S (kidney size, blood flow): good screening test (operator dependent) CT or MR angiography (effective noninvasive tests to establish presence of stenosis) ACE inhibitor renography (ie. captopril renal scan) renal arteriography (gold standard)
ts
Investigations
Cancbin: llenllftly lt'I'IKIArizlti carries 5ignificlnt ri5b Mhoullll'( beneil Ill nnl fln:tian oriiCOIIdlly11111:c1n1 cam!Bid1D
lllldUifliiiPI'
Treatment medical therapy, percutaneous angioplasty + stent, surgical revascularization little or no benefit if therapy is late Le. kidney is already shrunken. However, therapy can be considered to save the opposite kidney if normal
3. RENAL VEIN THROMBOSIS
Etiology hypercoagulable states (e.g. nephrotic syndrome, especially membranous), ECF volume depletion, extrinsic compression of renal vein, significant trauma, malignancy (e.g. RCC), sickle cell clinical presentation determined by rapidity of occlusion and formation of collateral circulation acute: nausea/vomiting, flank pain, hematuria, elevated plasma LDH, rise in Cr, sudden rise in
proteinuria chronic: increasing proteinuria and/or tubule dysfunction
Investigations renal venography (gold standard), CI' or MR angiography, duplex Doppler U/S
Treatment anticoagulation with heparin then warfarin (1 yr or indefinitely, depending on risk factors)
NP32 Nephrology
Vascular Diseasea of the Kidney/Systemic Diseases and the Kidney
Toronto Notes 2011
Small Vessel Disease1. HYPERTENSIVE NEPHROSCLEROSIS see Hypertension, NP32....... 1:11111 ..W*'ilm.Mid2lXXl; 17;133:600-3 cohort-wMII follow " of 5-I 0years. Pllilnll: 145 paliiJU w iducilnxllnnlllllll crisis w11a inl6im111d li&2paaMh IICiari*w. wllo did 11111 hm ranll crilil. need fordBy$is IIIII Ill\' dalllllllllllg paliiJU Mil nlllli crilil . . . .: Six!y-0111 J*CII1I ol ptltilutlwitl-1 crilil good outx:ons (55 hid 110 diltflis 111d 3418C8ivld 11mPQIIIY dilllvsist onlv 4 rl 1bese pllierQ chronic rellll fliUe 111d .-m-t dilllysil. Gllltlrlllln 50'1. ol .. patiarG wllo inibllv dilllysi5 3'II I Bmon1hs 1111r. Farrt.nt dilytisw .t, dBIIII occ:uned in 31% ollhB plllilds. c.Jailn: llllnllcrisis Cll1 M1111111Q11dwhn llypWnliol contraiiiiiMIII ACE illlibibn
2. ATHEROEMBOLIC RENAL DISEASE progressive renal insufficiency due to embolic obstruction of small and medium-sized renal vessels by atheromatous emboli spontaneous or after renal artery manipulation (surgery, angiography, percutaneous angioplasty) anticoagulants and thrombolytics interfere with ulcerated plaque healing and can worsen disease presentation: acute or chronic, progressive renal dysfunction, labile hypertension, extrarenal atheroembolic disease support diagnosis (livedo reticularis is a classic sign) pathology: needle-shaped cholesterol clefts (due to tissue-processing artifacts) with surrounding tissue reaction in small/medium-sized vessels no effective treatment; avoid angiographic and surgical procedures in patients with diffuse atherosclerosis
3. THROMBOTIC MICROANGIOPATHY a spectrum which includes HUS, TTP, DIC, post-partum renal failure renal involvement more common in HUS than TTP renal involvement characterized by fibrin thrombi in glomerular capillary loops arterioles treatment depends on cause supportive therapy TTP: plasma exchange, corticosteroids (splenectomy and rituximab if refractory) avoid platelet transfusions and ASA
.... ..........
NEJM mrl; 251:2562-75 s.dJ; rftorrimd controlled iill will IZIIIOIIIIfolcJw.q). l'llilnla: 1645 p!lients scheduled ta receilt 1
.........: NJrcoplalollfe COrticollaroidiiMd ailher.l) lillndl'd dose cyct)IJIQ!ila; dlcianb iniLoction; 3) lowdou--.sv.idl dBcianb iniLoction; 4) low doll illlhls Mil
4. SCLERODERMA 50% scleroderma patients have renal involvement (mild proteinuria, high Cr, HTN) histology: media thickened, "onion skin hypertrophy of small renal arteries, fibrinoid necrosis of afferent arterioles and glomeruli 10-15% scleroderma patients have a "scleroderma renal crisis": malignant liTN (usually within the first few years), ARF, microangiopathy, volume overload, visual changes, HTN encephalopathy renal involvement usually occurs early in the course of illness treatment BP control with ACEI slows progression of renal disease
Eslinalld Coc:tr.llft-Gd GfR 12 mollllulllrbnplllllllion. ....:1111 TICIGiilllllllm llllowllllignific:lndv hifi!BJ IGI'R It 12IIU!Ihl COIIfllld 111111 111111' M111 (65.4 mVmin VI. 51.1, 51.4, 56.7for IIIIlS I, 2. 4 reepeciMiy. lie TIICIIhlsn llso I'-d dlclllllld IIIII riiCID 11jel:tion Ill 6 n.dls ll1d 12111111111svs. II M111 (p30 minutes without spontaneous cessation or recurrent seizures without full return to consciousness inter-ictally
ClassifieationSeiZU111UnpriiVOksd
...I
I
Provoked
...
+'. Panial- Simpla
can secondarily become - - - - - - - - - - - - - - - - - Generahzad
t.I
...I
I
Complex
...
...Abet nee
Motor Sensory
Autonomic
+
Pwychiatric
...
l
Convulsive
...I
Fevar Metabolic Trauma
Clonic
Figura 1D. Classification of SaizurasStroke is the most common cause of late-onset (>50 'f8lll' of age) seizures,accounting for 53-BO'K. of c__
Tonic
+ +
Tonio-Cionic
Myoclonic
+ ...
Atonic
Etiology idiopathic identifiable etiology: vascular, congenital, neurodegenerative or other neurologic disorders, neoplasm, trauma, childhood epilepsy syndromes, infection, metabolic, toxins, genetic cryptogenic
Signs and Symptoms generalized seizures tonic-clonic (grand mal): prodrome of unease or irritability hours to days before the attack tonic ictal phase: tonic muscle contractions, arm flexion and adduction, leg extension, 'cry' as respiratory muscle spasm and air is expelled; lasts 10-30 seconds clonic ictal phase: clonus involving violent jerking of face and limbs, tongue biting, incontinence; 65 years of age have dementia common etiologies: 60-SO% Alzheimer's Disease (AD); 10-20% vascular dementia 85 years of age accounts for 60-80% of all dementiasRisk Factors
family history of AD head injury
low education level smoking aluminum (controversial) Down's syndromeSigns and Symptoms
cognitiveimpairment memory impairment for newly acquired information (early) deficits in language, abstract reasoning, and executive function psychiatric manifestations major depressive disorder {5-896) psychosis (20%) motor manifestations {late) parkinsonism (consider Lewy body disease)Investigations
perform investigations to rule out other causes of dementia as necessary EEG: generalized slowing (nonspecific) MRI: dilatation oflateral ventricles; widening of cortical sulci SPECT: hypometabolism in temporal and parietal lobes
Treatment
acetylcholinesterase inhibitors have been shown to improve cognitive function donepezil rivastigmine (Exelon), galantamine (Reminyl) relative contraindications: bradycardia, arrhythmia, CHF, CAD, asthma, COPD, ulcers, or increased risk of ulcers and GI bleeding galantamine is contraindicated in patients with hepatic/renal impairment memantine (Ebixa) is an NMDA-receptor antagonist that has some benefits in later stage AD other - although efficacy not proven ginkgo biloba Vit E (caution: >400 IU/day associated with excess mortality; Ievell evidence) symptomatic management low dose neuroleptic trazodone for sleep disturbance antidepressantsPrognosis
progressive mean duration of disease 10 years
Lewy Body Disease (LBD)Definition
progressive cognitive decline interfering with social or occupational function; memory loss may or may not be an early feature one {possible LBD) or two {probable LBD) of the following: fluctuating cognition with pronounced variation in attention and alertness recurrent visual hallucinations parkinsonism
Nl4 Neurolo8Y
Behavioural Neurolo8Y
Toronto Notes 2011
Etiology and Pathogenesis Lewy bodies (eosinophilic cytoplasmic inclusions) found in both cortical and subcortical structures Epidemiology 15-25% of all dementias Signs and Symptoms :O.uctuation in cognition with progressive decline visual hallucinations parkinsonism repeated falls sensitivity to neuroleptic medications (develop rigidity, neuroleptic malignant syndrome, extrapyramidal symptoms) REM sleep disorder Treatment acetylcholinesterase inhibitors (e.g. donepezil) Prognosis typical survival3-6 years
Frontotemporal Dementia (FTD)Definition progressive dementia characterized by core symptoms of either disinhibition and emotional lability or of apathy and detachment Etiology and Pathogenesis gross pathology atrophy of frontal and temporal poles microscopic pathology Pick bodies (intraneuronal inclusions containing abnormal Tau proteins) Epidemiology 10% of all dementias Signs and Symptoms core features behavioural disorder impairment of personal conduct and of regulation of social interactions decline in personal hygiene and grooming mental rigidity/inflexibility perseverative and stereotyped behaviour speech and language altered speech output (economy or pressure of speech) echolalialperseveration physical signs primitive reflexes (ie. pout, grasp, palmomental, glabellar) parkinsonism Investigations MRI/SPECT - frontotemporal atrophy/hypometabolism
Creutzfeldt-Jakob Disease (CJD)Definition rare degenerative fatal brain disorder Pathophysiology prion proteins causing alterations in the brain such as spongiform changes, astrocytosis and neuronal loss Epidemiology rare (1 in a million), peak incidence between 50-70 years old
Toronto Nota 2011
Neurology NlS
Clinical Presentation sparadk CJD: rapidly progressive demenling illness causing death within months, associatedwith myoclonus
cerebellar ataxia cxtrapyramidsl signs aldnelk mutism and cortical bUndness sometimes occurfatalwlthinlyear EEG: triphasic compleus
Diagnosis rule out treatable dementia, neurologic exam, EEG, MRI only wsr.y to confirm diagnosis is brain biopsy/autopsy
1\fpes
sparadk CJD: most common form (8596), no risk facmrs hereditary CJD: family history or tests positive fur genetic mutation (5-10%) acquired CJD: transmitted via exporure to prion in nervous system tissue (90% of essential tremor does not need treatment.
Differential Diagnoses 1. Tremor: a. Postural: physiologic, anxiety, sedative/alcohol withdrawal, drug toxicity, heavy metal poisoning, carbon monoxide poisoning, thyrotoxicosis, benign essential tremor, cerebellar, Wilson's disease benign essential tremor is a common autosomal dominant trait that presents as a bilateral postural tremor of the vertical axis, especially in the upper extremities b. Intention: brainstem lesion, cerebellar lesion, alcohol, anticonvulsants, sedatives, Wilson's disease c. Resting: Parkinsonism, Wilson's disease, mercury poisoningTable 17. Approach to TremorsResting Body Part Characteristics Worse with Associated Sx DDx Distal UE 3-7Hz pill rolling Rest while concentrating "TRAP" IPD, Parkinsonism, Wilson's disease Sinemet, anticholinergics, surgery, DBS Postural Uf/head/voice 612Hz fine tremor Sustained posture (outstretched arms} Autosomal dominant FHX
Intention Anywhere sensory) slowing, decreased
GBS is a neurological emergency due to risk of imminent raspinrtory failtn.
....
,,
F-wave subtypes 1. Acute inflammatory demyelinating polyneuropathy (AIDP) 2. Acute motor-sensory axonal neuropathy (AMSAN) 3. Acute motor axonal neuropathy (AMAN) treatment disease specific: IVIg or plasmapheresis nonpharmacologic: admit and monitor vital signs and vital capacity due to risk of respiratory failure, manage dysautonomia, manage pain prognosis nadir of symptoms at 2-3 weeks, with resolution at 4-6 weeks 5% mortality (higher ifiCU), 7-15% permanent substantial deficits Diagnostic Approach to Peripheral Neuropathies 1. Differentiate: motor vs. sensory vs. autonomic l. Pattern of Deficit: symmetry, focal vs. diffuse, upper vs. lower limb, cranial nerve involment 3. Tempo: acute to chronic, relapsing remitting vs. constant 4. Good History: PMH, detailed family tree, exposures (e.g. insects, toxins, sex. travel), systemic symptoms 5. Detailed Peripheral Neuro Bum: LMN findings, differentiate between root and peripheral nerves, check cranial nerves, check respiratory status
Miller-RICIH!r Y11rimt af GBS - Triild 1. Ophthalmoploqill
2. Ataxia 3. Arvllexil
....
,,
Mg and pi1Ui111apilemillalld tD morv rapid improvement, less intensive care
and less ventillllion, but do not changemortality or ralaps1 ram.
N32 Neurolo8Y
Neuro-oncology/Neurom115Cular Junction Diseaaa
Toronto Notes 2011
Neuro-oncologyParaneoplastic SyndromesDefinition uncommon complication of cancer; often is the presenting complaint
Pathophysiology likely an autoimmune attack on the nervous sym:em by tumour antigens
Associated Neoplasms small cell lung cancer: cerebellar degeneration, encephalitis, opsoclonus-myoclonus,retinopathy, neuropathy, Lambert-Eaton syndrome breast: cerebellar degeneration, encephalomyelitis, opsoclonus-myoclonus thymoma: myasthenia gravis other syndromes: necrotizing myelopathy, motor neuron syndrome, neuropathies, mononeuritis multiplex, polymyositis and dermatomyositis, encephalitis
Investigations antibodies commonly ordered include anti-Hu, anti-Ri and anti-Yo
Treatment unsatisfactory and often palliative. Options to consider are steroids, IVIg, plasmapheresis and treatment of malignancy
Tumours of the Nervous System see NS9
Neuromuscular Junction DiseasesClinical Approach to Disorders of the Neuromuscular JunctionTabla 19. Common Disorders of the Neuromuscular JunctionButuli1m
OculluAiulblr pamis
++ +N
++(early)
.....
', ..
Limb WIIDISS
htiguablity
Post-exen:ile enhlncement ReflexesANS anti:hulin. .ic Sx
+ + + +
+ ++
Dis1un of 1h1 niUilllllllscular junction typically feature prominent fatiguability.
++GISSx
SansarySx
Associated conditionsRapatilivll EMG stimulatilll
Thymoma
Small cell carcinoma
"'
1' (rapid sti'I'IJiation)-.1- (slow
1' (rapid stimulation)>lr (slow stimulation)
Myasthenia Gravis (MG)Etiology and Pathophysiology damage and blockade of post-synaptic acetylcholine receptors by specific antibodies 15% of patients with myasthenia gravis have associated thymic neoplasia, 85% have thymic
hyperplasia autoimmune disorder
Epidemiology bimodal age of onset - 20's (mostly women) and 60's (mostly men)
Toronto Notes 2011 Signs and Symptoms
Neuromusc:ula.r Junction Diseasea
Neurology N33
see also Table 19 fatiguability and weakness of skeletal muscles without reflex, sensory, or coordination abnormalities typically ocular (diplopia/ptosis) -+bulbar (dysarthria/dysphagia) -+ necldlexors/extensors -+ proximal limbs respiratory muscle weakness may lead to respiratory failure
Myasthenia Gravis is a neurological emergency due to 1he risk of imminent rnpillllory failure I
....
,, ,,
Investigations edrophonium (Tensilon) test -can result in respiratory difficulty so have crash cart nearby assess for improvement over 2 minutes following edrophonium injection EMG repetitive stimulation -+ decremental response single fibre electromyography shows increased jitter (80-10096 sensitivity) anti-acetylcholine receptor antibody assay (70-80% sensitivity) MUSK antibody may be used if seronegative for AChR antibody CT/MRI to screen for thymoma/thymic hyperplasiaTensilon is a drug 1hat inhibit$ acltylcholinestlrllsl. It improvM mJscll function immadilltaly in my811henia
gravis, but not in cholinergic crisis.
....
Treatment thymectomy 8596 of patients show improvement or remission symptomatic relief acetylcholinesterase inhibitors (e.g. pyridostigmine) does not affect primary pathologic process -+ rarely result in control of disease when used alone immunosuppression steroids are mainstay oftreatment - 70-80% remission rate azathioprine, cyclophosphamide and mycophenolate as adjuncts to steroids or as steroid sparing therapy short-term immunomodulation (for crises) IVIg and plasmapheresis
zClinical Forms rrf Mpltllenil GriVis 1. Ocular [15"'} 2. Gene1111ized (85%1
Prognosis 3096 eventual spontaneous remission
Lambert-Eaton Myasthenic Syndrome (LEMS)Etiology and Pathophysiology downregulation of presynaptic voltage-gated Calcium channels 2 to specific channel binding antibody causing decreased amounts of ACb released into the synaptic cleft 50-6696 are ultimately associated with small cell carcinoma of the lung
Signs and Symptoms weakness of skeletal muscles without sensory or coordination abnormalities reflexes are diminished or absent, but increase after active muscle contraction bulbar and ocular muscles affected in 25% prominent anticholinergic autonomic symptoms (dry mouth >impotence> constipation > blurred vision)
....
,,
Lambert-Eaton myas1hanic syndrome can be differentiated from myasthenia Qlllvis, by 1ha phenomenon of postexercise facilitlltion.
Investigations edrophonium test (see Myasthenia Gravis) -+ no response EMG: rapid (> 10Hz) repetitive stimulation -+ incremental response screen for malignancy, especially small cell lung cancer post-exercise facilitation- an incremental response to repetitive stimulation due to presynaptic calcium accumulation
Treatment tumour removal acetylcholine modulation increased acetylcholine release (3-4 diaminopyridine) decreased acetylcholine degradation (pyridostigmine) immunomodulation steroids, plasmapheresis, IVIg
N34 Neurolo8Y
Myopathiea
Toronto Notes 2011
MyopathiesClinical Approach to Muscle DiseasesTable 20. MyopathiesEtiology lnlllmmiiDry Polymyositis Mya[gies Pharyngeal involvement Mya[gias Similar to polymyositi& Characteri&tic r.&les Can be paraneoplastic
Ksr lnvatigations1' CK Biopsy: endomesial Necrosis 1' CK Biopsy: parifasciculll' atrophy
....
',rnsen.tion
Dermatomyositis
lmporu,nt lnfanution to Reganllnf Myapllthilll Weakness: proximal > distal
Pain: myalgias, but no impaired MyotDnil [difficulty with relaxldioo)
Sarcoido8is Inclusion body myositis
ACE IIMII Biopsy: IJliiUIOIIllls
Weak quads and deep finger flexorsSee Endocrinology
1' CK Biopsy: ilclusion bodias TSH, serum cortisol, calcium panel Toxicology Biopsy: selective loss of thick Myosin filaments
.....
',
Endoc:rin1
Thyroid (1' or -1-) Cushing's syndrome Parathyroid (1' or -1-) Medication Critical illness myopathy
Myoplllllisl1118 chlllle1llrizad by prominent symmetric proximal
Medication or toxin history
weakness end lbsant SIIIIIO!'f chlngal.
.....
',Hereditary Dystrophy
ICU patient Hx steroid& and nondepolarizing palltfzing agents Faiure to ween from ventilationMya[gies Inflammatory myopathy onset {Duchenne and Becker) Prograssiw proxi11111l muscle -knass pseudohypertrophy Distal myopathy Myotonia Genetic anticipation Exercise-related rnyalgias, cramping, and myoglobumimria Episodic W8ilkness between attacks
Parasitic, bactErial, or vinll Duchenne
1' ITI'fl9obin Biopsy: abnormal dyttrophin Staining Genetic testing
Good Cll..ti- to Alina Proximal
wen-s
Legs: climbing slllirl, stand from sit Anna: n111ch above hlllld, wash hair
BecksrMyotonic dystrophy
.....
',
Hereditary Mltlbolic
McArdle's
Common Mellicalio1111bat Cauu Mpptllhy Steroids, mrtins and IIIT!mnmrBis
1' lactate 1' serurnturinary myoglobil Pllst-sxen:ise 1'cr-I-K Increased lactate Biopsy: ragged red fibres
Heredililry Periodic Parllylil Heredililry
Periodic paralysis MERRF MELAS ICI!ImsSayre
Mitochandriil
Ptosis, conmon Proximal > distal myopathy Exercise intolerance Rhabdomyolysis
Abbreviltion5: MBliiF -ITilochoncnl encephlllomyoplllhy slrulie-like episodes
rauged llld fibe11; MELAS- mitochondrial encepllllomyopathy, lactic I!Cifbis, and
Polymyositis/Dermatomyositis see RH13
Myotonic DystrophyEtiology and Pathophysiology unstable trinucleotide repeat in DMK gene (protein kinase} at 19ql3.3 number of repeats correlates with severity of symptoms; autosomal dominant Epidemiology most common adult muscular dystrophy prevalence 3-5/100 000 Signs and Symptoms appearance: ptosis, bifacial weakness, frontal baldness {including women), triangular face giving a drooping/dull appearance
Toronto Notes 2011
Myopathies/Cerebellar Disorders
Neurology N35
physical exam distribution ofweakness: distal greater than proximal (in contrast to other myopathic disorders) myotonia: delayed relaxation of musclc:s after exertion (elicit by tapping on thenar muscles with hammer) cardiac: 90% have conduction defects ( 1 heart block; atrial arrhythmias) respiratory: hypoventilation 2 to muscle: weakness ocular: subcapsular cataracts, retinal degeneration, decreased intraocular pressure EMG: subclinical myotonia -long runs with declining frequency and amplitude
Treatment no cure management of myotonia: phenytoin
Duchenne and Becker Muscular Dystrophy see Pediatrics, P46
Cerebellar DisordersClinico-Anatomic Correlations vermis: trunk/gait ataxia cerebellar lobe (i.e. lateral): tremor, rebound phenomenon, dysarthria, dysdiadochokinesis, nystagamus Symptoms and Signs of Cerebellar Dysfunction nystagmus: observe on extra-ocular movement testing (most common is gaze-evoked nystagmus) dysarthria (ataxic dysarthria): abnormal modulation of speech velocity and volume- elicit scanning/telegraphic/slurred speech on spontaneous speech (see Dysarthria, Nl9) ataxia: broad-based, uncoordinated, lurching gait dysmmetria: irregular placement ofvoluntary limb or ocular movement dysdiadochokinesis: unable to perform rapid alternating movements (e.g. pronationsupination task) postural instability: look for truncal ataxia on sitting (titubation =rhythmic rocking of trunk and head); look for difficult tandem gait and broad based gait intention tremor: elicit on finger-to-nose testing- typically orthogonal to intended movement, and increases as target is approached hypotonia: decreased resistance to passive muscular extension- occurs immediately after injury to lateral cerebellum pendular patellar reflex: knee reflex causes pendular motion ofleg occurs after injury to cerebellar hemispheres rebound phenomenon: overcorrection after displacement of a limb (with both arms extended --+ pushing both will cause one to rebound up if there is lesion on that side)
Wernicke-Korsakoff Syndrome deficiency of thiamine due to alcohol abuse acute: apathy, confusion, decreased EOM, ataxia (truncal and gait) without treatment progresses to encephalopathy and ultimately death treatment: thiamine 100 mg Korsakoff's syndrome: progressive decline ofboth anterograde and retrograde memory note that alcohol can also cause a cerebellar ataxia separate from thiamine deficiency. The ataxia can be due to cerebellar atrophy or alcohol polyneuropathy
Cerebellar AtaxiasCongenital Ataxias early onset nonprogressive ataxias associated with various syndromes as well as development abnormalities (e.g. Arnold-Chiari malformation, Dandy-Walker cysts) Hereditary Ataxias autosomal recesaive: includes Friedreich's ataxia, ataxia telangiectasia, vitamin E deficiency Friedreich's ataxia: prevalence 2/100 000; onset between 8 and 15 years signs: gait and limb ataxia, weakness, areflexia, extensor plantar reflex, impaired proprioception and vibration death in 10-20 years from cardiomyopathy or kyphoscoliotic pulmonary restriction autosomal dominant: spinocerebellar ataxias (SCA.s) of which 30 exist, most are CAG repeats
N36 Neurolo8Y
Cerebellar Disorden/Vertigo/Gait Diaturbances/Pain Syndromes
Toronto Notes 2011
Acquired Ataxias neurodegeneration (e.g. multiple system atrophy) systemic: alcohol, celiac sprue, hypothyroidism, Wilson's, thiamine deficiency toxins: carbon monoxide, heavy metals, lithium, phenytonin, solvents vascular: infarct, bleed, basilar migraine autoimmune: MS, Miller-Fischer (GBS) children: tumours, post-viral
Vertigo see Otolaryngology, OT12
Gait DisturbancesApproach to Gait Disturbances I. Length of stride if small paces - look at posture if stooped with no armswing- Parkinsonian gait look for other signs of extrapyramidal disorders if upright with exaggerated armswing - Marche a petit pas due to diffuse infarction of both cerebral hemispheres (lacunar)
r-t,
CENTRAL MOTOR SYSTEMS 3 compnnb tu til cantrol af pit 1. Pyramidal: main ouUiow from cor1ex to spinal cord 2. Extrapyramidal: bani ganglia inhibita BJa:llll mCMimanb; 3. Clrlblllum: afflcts coordination of
2. If normal stride length, look at width between feet if wide-based- ataxia if high stepping and positive Romberg- sensory ataxia loss of joint position sense (+ve Romberg) if wide based without high stepping - cerebellar ataxia veers to side of the lesion if scissoring of legs or toe walking- spastic gait bilateral circumduction due to spastic paraparesis from cerebral palsy, multiple sclerosis or cord compression 3. If normal width, look for height of step if high stepping bilaterally- bilateral foot drop if feet barely leave ground or disjointed movement - magnetic/apraxic gait frontal lobe pathology due to normal pressure hydrocephalus or cerebrovascular disease4. If no high stepping, lookfor stabllity of pelvis if rotation of pelvis - waddling gait
proximal muscle weakness due to congenital deformity or myopathy5. If no waddling, look at symmetry if asymmetric - antalgic gait, deformity or hemiparetic gait antalgic gait is due to pain from an MSK problem hemiparetic gait involves a foot drop and circumduction of spastic leg due to UMN lesion
6. If movement is elaborate and inconsistent, especially when being observed. conaicler functional pit rule out an odd gait due to chorea from Huntington's disease
Pain SyndromesApproach to Pain Syndromes
...._,, Pinprick CIIUUI sharpnns rnldimd byJIIJfibani Pain to damage is mediated by Cfibres
Definitions Nociceptive pain: pain arising from normal activation of peripheral nociceptors Neuropathic pain: pain arising from direct injury to neural tissue. bypassing nociceptive pathways Spontaneous pain: unprovoked burning, shooting, or lancinating pain Paresthesiae: spontaneous or evoked abnormal nonpainful sensations (e.g. tingling) Dysesthesiae: spontaneous or evoked pain with inappropriate quality or excessive quantity Allodynia: a dysesthetic response to a nonnoxious stimulus Hyperalgesia: an exaggerated pain response to a noxious stimulus
Toronto Notes 2011
Pain Syndromes
Neurology N37
Medical Pain Control primary analgesics: OTCs, opiates adjuvants: antidepressants (TCAs, SSRis), anticonvulsants (gabapentin, carbamazepine), baclofen, sympatholytics (phenoxybenzamine), a2-adrenergic agonists (clonidine, pregabalin)
Surgical Pain Control direct delivery: implantable morphine pump central ablation: stereotactic thalamotomy, spinal tractotomy or dorsal root entry lesion peripheral ablation: nerve blocks, facet joint denervation deep brain stimulation (DBS) or dorsal column stimulation
Neuropathic PainDefinition pain resulting from a disturbance of the central or peripheral nervous system
Symptoms and Signs hyperalgesia/allodynia subjectively described as -burning, heat/cold, pricking, electric shock, perception of swelling, numbness (Le. stocking/sock distribution) can be spontaneous or stimulus evoked distribution may not fall along classical neuro-anatomicallines
Associated Issues sleep difficulty anxiety/stress/mood alteration sexual dysfunction
Causes of Neuropathic: Pain peripheral neuropathy systemic disease - diabetes, thyroid disease, renal disease, rheumatoid arthritis nutritional/toxicity- alcoholism, pernicious anemia, chemotherapy infectious - HN trauma - post surgical, nerve injury nerve root: post-herpetic neuralgia, cervical and lumbar radiculopathies, tic douloureux (see Trigeminal Nerve, Nl8), plexopathies central: MS, post-stroke, phantom limb, spinal cord injury Complex Regional Pain Syndromes (see N38) malignancy
Treatment pharmacotherapy: TCA. SNRI, anticonvulsant, long acting opiate, topical lidocaine, capsaicincream, intrathecal opioid or clonidine, Botox, nerve block surgical therapies: dorsal column neurostimulator, DBS (thalamus) other therapies: neuropsychiatry - cognitive behavioural theraphy, psychotherapy rehabilitation - physiotherapy CAM - acupuncture, meditation, massage therapy, TCM
Tic Douloureux (Trigeminal Neuralgia) see Trigeminal Nerve, N18
Postherpetic Neuralgia (PHN)Definition pain persisting beyond 3 months in the region of a cutaneous outbreak ofherpes zoster
Etiology and Pathogenesis destruction of the sensory ganglion neurons (e.g. dorsal root, trigeminal, or geniculate ganglia) secondary to reactivation of herpes zoster infection
Epidemiology 10-15% of all patients with cutaneous herpes zoster >80% of herpes zoster infected patients >80 years old
N38 Neurolo8Y
Pain Syndromes
Toronto Notes 2011
Signs and Symptoms types of pain: constant deep ache or burning. intermittent spontaneous lancinating/jabbing pain, allodynia distribution: thoracic > trigeminal > cervical > lumbar > sacral Treatment acute herpes zoster early treatment with antiviral agents (acyclovir; longer-acting famciclovir and valaciclovir more effective) may prevent PHN in patients over 50 years PHN medical: TCA, pregabalin, gabapentin, opiate, lidocaine patch, intrathecal methylprednisolone surgical: spinal tractotomy, dorsal root entry zone lesion
Complex Regional Pain Syndromes (CRPS)Definitions CRPS is a pain syndrome characterized by the following 1. presence of an initiating noxious event 2. continuing pain, allodyrua, or hyperalgesia with pain disproportionate to inciting event 3. evidence during the course of symptoms of edema, changes in skin blood flow, or abnormal vasomotor activity 4. absence of conditions that would otherwise account for degree of pain and dysfunction Classification CRPS type I (reflex sympathetic dystrophy): minor injuries of limb or lesions in remote body areas precede onset of symptoms CRPS type II (causalgia): injury of peripheral nerves precedes the onset of symptoms Signs and Symptoms stage I (acute) pain: burning or aching disproportionate to initial injury autonomic: edema and temperature inequality stage II (dystrophic) pain: constant and increased by stimulus to affected part autonomic: osteoporosis, cool hyperhydrotic skin, hair loss, cracked/brittle nails stage III (atrophic) pain: paroxysmal spread autonomic: thin, shiny skin, thickened fascia with contractures, bony demineralization Investigations diagnosis is clinical trial of differential neural blockade may be helpful Treatment medical: phenoxybenzamine (sympatholytic) surgical: paravertebral sympathetic ganglion blockade
Thalamic Pain (Dejerina Roussy Syndrome) - -Definition hypersensitivity to pain as a result of damage to the thalamus Etiology and Pathogenesis injury to ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei of the thalamus ischemic stroke hypertensive vascular hemorrhage Signs and Symptoms begins with hemianesthesia then persistent spontaneous burning contralateral to lesion altered response to light cutaneous and deep painful stimuli Treatment medical: amitriptyline, anti-convulsants surgical: stereotactic thalamic stimulation (may increase sensory deficit)
Toronto Notes 2011
Headache
Neurology N39a.lllliaal cmc.J Eumilllllign: O.llil Pllilnt wilb 11Hdde .... a..,. NllllJWA 2006; 2!1&:1 274-83
HeadacheClinical Approach to HeadachesInvestigations good history and physical to rule out serious causes of headache important aspects of neurologic exam: LOC and MSE, pupils (symmetry), fundi (papilledema, retinal hemorrhages), pronator drift, meningismus, deep tendon reflexes and Babinski, gait indications for a new-onset headache, worst headache of life, thunderclap headache, headache with worrisome symptoms (fever, meningismus, altered LOC, focal neurologic deficits, trauma, papilledema, morning headache) if CT is negative but suspicion of SAH or meningitis, perform a lumbar puncture
N......,nnmanic: p-
Dnltlil!lllillllwilb ........... The most of..- for dilgnosing nipile i$ .urrrrm.d by 11-. P(Utling
'*"
u-
a - 4inl1ion of 4-72
UnilideriiiOCIIion
cr
N - Nlu or-womiling D- Disllblingint!llsily
Table 21. Headaches- PrimaryTCIIIioa-Typa PrevalenceMigrma
..............,
ThaiR far dafiW or polllil1i n-i11111inl dill!jlllllii VlrillwM!I U.lllmblr rlfiiUM pr8I8IE Mdl 3111d feiW U.Llls ... 24 {1.5-3181. 3.5 {1.3-9.2111111 0.41 {0.32-0.521 TllpiC1ivltf. Dnlllil , . . .... h...... IIIII
Clustar M Nona Bilateral frontal MinLIII!s-days lndual; worse in PM Band-like; constant Mild-modarata DepressionAnxiety
12% 10-30 F>M
Aga of OlllltSexBia Family HistaiY
M>F
+++Uniateral>bilateral Fronto-tenwal Haurs-days Gradual; worse in PM Tlrobbing Modarata-severa Noise Light Strainilg Coujing Activity Rest Nausi!I1/VDmiting Photo/phonophobia Aura Muscle tension in scall)'neck Tandar scalp artaias AcuteRx MA NSAIDS Triptans Ergotamine Prophylaxis l'ropnllolol TCA Anticonvulsents
+Retroorbilll 10mh-2. haurs
l.ocatiCIIDul'llion Onset/CGune
The prawlence rl ii'Uicllnill pllllology {!111111 problliiitylwrias lnlll011 v.1lh dlronic helldldle 1he plellllence is l.l'J. {0.77-1.11\).ln Ylll niglint-typl lllldlclw the prMiince is Howavll. inlhose prasal1ing wi1h new lllldlclw the prMiince is 32'Jo in 1hose jiiUidiiQ Ylilll t!UIIIarcllp hlllldlchl the prMimct is 43\ {211-611\). Ill th8le dilllrant popullbs. 110 clinical flllfln was found lo hlllllful inlllivJ imcrlrill pethoQ in a 1118111iniiUMYHawM!. -a indivi!UI c1inicll IIU.ns Will luund 1o 1xt ]IIICictive of lignili:lnt petholoQr.c:QI8r-tp haadache
Daily headache for weeks, months, nocturnalConstant, aching. stabbing S8\111'8 (waklls from sleep) Light
abnonnlllraJroiDQicll1111111111ddneli-typl hlldlch1
DualitySeverity Pravoldng
10.7 {21-52) 5.3 {2.4-12) 3.8 {2.0-7.11
IQUIMbld
lllldlclwv.tiilllldlclw Mil wmiling
3.2 {1.66.61 2.3 {1.4-UI1.8 {112.61
EtOH
Noise Hunger Slaap deprivation Pallating Rest No vomiting No photophobia Muscle tension i'1 Non1)harmacological Psychological counseling Physical modalities (e.g. heat, massage) Phannacological Simple analgesics Tricyclic antidepressants
Walking around
ARoc:iltad Sx
Red watery eve Nasal congestion or rhinoi'Thea Unilateral Homer's Red watery eye, rhinorrhea Eyaid !hopAcute Rx Oz Sumatriptan (IIIISII or injection) Prophylaxis Verapamil Lithium Methylsergide Pnmisolone
Six Dl Seria Halldac.._ lnaluda: 1. The lUdden onset Ill a savm
headache;
Pllysicll SignsMIRII!IIdllnt
neurolovic deficibi; or 3. New headaches beginning after age 50.
2. AccomplfTYing impaired mental sbllus, uizul"ls, or focal
fl-.
Table ZZ. Headaches- SeriousMeningllllrrilatilll Incidence Age of Onset SP:Bils Locetion Duration Onset/Coull8Quilty
...creased lllraa'anill Pressure