Neurologic Complications of Neurologic Complications of Systemic DiseaseSystemic Disease

October 3rd 2012Robert 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

• Appreciate “common presentations” of the diseases seen in Internal Medicine / Rheumatology clinics or in consultation– Emphasis on multi-media, neuroimaging and clinical

reasoning through 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

“Neurological Borderlands”

• Studying the impact of systemic diseases on the nervous system allows for– Consolidating knowledge 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

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

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

Outline1. Neurologic Complications of Hepatic Failure

– Hepatic encephalopathy, cirhosis and ALF2. Alcohol and the nervous system3. Neurogastroenterology

– Mini-review of a few ultra-precise topics4. Neurologic Complications of Renal Failure5. Systemic Inflammatory Diseases

– Sarcoid– Sjögren’s Syndrome– RA– SLE

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?1. Asterixis2. Bradykinesia3. Dysarthria4. Seizures5. Somnolence

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?1. Asterixis2. Bradykinesia3. Dysarthria4. Seizures5. Somnolence

CASE 1

Neurologic Manifestations of Hepatic Failure / ALF

Clinical Clues

• Background knowledge of stigmata of chronic liver disease may help when diagnosis is ambiguous

Hepatic FailureHepatic 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

Altered LOC in Liver Patient

• Ddx– Hypoglycemia– Sodium disturbance– Epileptic – Cerebral edema– Hypoxia (unwitnessed cardiac or pulmonary arrest)

• Intoxication or OD

– Wernike– ICH (coagulopathic)

“Don’t do something, just stand there......”

Pallidal hyperintensities on T1

Reflects a significant porto-systemic shunt, NOT hepatic encephalopathy

Mn deposition (reduced excretion in bile)

90% of patients

AJNR Am J Neuroradiology May 2012

Hypoglycemic Coma MRDWI is key sequence

NB. Study excluded cardiac / respiratory arrest

CPM: note DWI + and location

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

IIII

Hepatic Failure / DiseaseHepatic Failure / Disease

Grade II•Asterixis•Brady•Rigidity•Tremor•Cerebellar dysarthria•Ataxia

Grade II•Asterixis•Brady•Rigidity•Tremor•Cerebellar dysarthria•Ataxia

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”

Principals of Management of Hepatic Encephalopathy (acute and chronic)

1. Look for source (occult bleed)2. Low protein in diet3. Lactulose PO or enema; titrate to 3+ soft BM per

day4. Antiobiotics

– Target urea producing bacteria in gut (Neomycin)5. Avoid benzodiazepines (heightened sensitivity); if

necessary try Oxazepam. – May need Flumazenil.

6. ICP management. Propofol, hypertonics.7. Consider porto-systemic shunting procedure

(TIPPS)8. Liver transplant (committee)

Practical Point

36 F overdose on acetaminophenCASE 1.5

Describe the pertinent findings.

• 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)

Acute Liver Failure (ALF)

“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

Practical Point

Brain (1998), 121, 127–133

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”

CASE 2

Accompanying MR BrainCASE 2

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

Practical Point

Wernike’s in Pregnancy

• Generally from hyperemesis graviderum• 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

Practical Point

Note DdxMolar pregnancyHyperT4Hepatitis

Neurologic Manifestations of GI Disease

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

CASE 3

Normal comparison

Gluten Enteropathy (Celiac)• Chronic immune-mediated systemic disease with

diverse manifestations including; GI, dermatopathy, neurologic dysfunction

– Diagnosis (in predisposed pt’s)– Serum markers +

– IgA tTG serology oror Anti-Endomysium Ab (IgA EMA)[Anti-gliadin IgG, 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 gutCan get neurologic involvement without gut

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

Serum from patients withSerum from patients withgluten ataxia reacts with Purkinje gluten ataxia reacts with Purkinje

cell epitopes cell epitopes

Perivascular inflammatroy Perivascular inflammatroy infiltrateinfiltrate

Perivascular TgPerivascular Tg Purkinje lossPurkinje loss

Name 5 auto-immune or immune mediated diseases (systemic or nervous system)

1. MG2. MS / ADEM3. GBS4. Dermatomyositis / polymyositis5. Devic’s disease (neuromyelitis

optica)6. Neuropsychiatric lupus7. Rhumatoid arthritis8. Sleroderma9. Sjogren10. Paraneoplastic syndromes +++

(NMDA-R encephalitis, SPS)11. Thyroid eye disease (Graves) or

Hashimotos’ (SREAT)

1. Vitiligo2. DM13. Psoriasis4. Celiac disease (ataxia,

neuropathy)5. IBD

Practical Point

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

CASE 4

Describe the most pertinent findings...

Neurologic Manifestations of ETOH Toxicity

ETOH and the nervous

system

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)

Practical Point

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%;

Neurologic Manifestations of Renal Disease

5-16% incidence of ARF in hospitalized patients

Mortality 20-51%

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

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

CASE 5

What is the next most important test in this patient’s management?

Normal neuroimaging (not shown)

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

Neurologic Complications

1. Manifestations of uremic state2. 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)

Disease Related

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

Disease Related• Encephalopathy

– ARF or CRF– Fluctuating LOC, disorientation, attention, concentration, sleep,

h/a, asterixis, myoclonus, sz, UMN signs• Uremic; neurotoxins• E+ derangement; hyperCa, Mg; hypoPO4, Na• Metabolic acidosis• Wernike’s• Hypertensive; PRES• Vascular event; SDH or SAH [low threshold to image]• Rx

? Disease Related• Ddx Encephalopathy in renal patient (cont)

• Rx• e.g., metoclopramide, phenothiazines, AEDs including

gabapentin, and opioids meperidine

• Bottom Line• Before concluding encephalopathy to be a clinical

feature of advanced uremia requiring renal replacement therapy, a careful search for other causes should be initiated

Correction of the underlying metabolic abnormality typically leads to resolution of symptoms

Disease Related• Cognitive impairment +/- Dementia

– 80% in those with CRF– Memory and executive dysfunction– Multifactorial

• Subclinical vascular cognitive impairment (same RF’s)• Inflammatory mediators• Anemia and relative hypoxia-emia• EPO• Hyperparathyroidism (HyperCa)

Cognition may improve after transplant; memory, concentration, psychomotor function, EEG/EP latencies

Disease Related• Cerebrovascular

– Ischemic and hemorrhagic• 4-10X risk compared to N controls

– Ischemia• ASO, CRF share common RFs

– DB, HTN, DLPD, smoking, ↑homocysteine– Anemia (independent RF for CVA)

– Hemorrhage– Plt dysfunction (poor aggregability)– HTN– PCKD (10X risk for aneurysms and dolichoectasia)– Antithrombotic agents used in HD to prevent fistula-thrombosis (heparin)

Disease Related

• Movement Disorders– Action myoclonus– Stimulus-sensitive myoclonus– “twitch convulsive syndrome” intense asterixis

and myoclonus accompanied by fasciculations, muscle twitching and seizures

– RLS 15-20%• Secondary to the renal disease, anemia +/- peripheral

neuropathy

All improve once metabolic disturbance under control or post-transplant

Disease Related• Focal mononeuropathies

– Susceptible to compression and ischemia in renal patients• Median, ulnar (UNE, UNW-from calcinosis), femoral

– Vascular “steal” phenomenon after fistula insertion• Polyneuropathies

– “Uremic neurotoxins”– 60% pt’s– Large and small fiber (including autonomic), cranial– May stabilize, even improve in dialysis (esp paresthesiae)

• Uremic Myopathy– 50% of pt’s on dialysis– “uremic toxins, vitamin D metabolism dysfunction, insulin resistence,

carnitine deficieny, malnutrition” all contribute]– Bx is normal or type II atrophy– Some improvement post-transplant

Neuromuscular Complications Proportionate to GFR

GFR Features Clinical<25ml/min (myopathy) Uremic myopathy

possible

Parallels decline in renal function

“myopathic” weakness; with wasting, poor endurance, and rapid fatiguing

Normal EMG / Bx (type II)

<12ml/min (polyneuropathy) NCS abnormalities

<6ml/min (polyneuropathy) Clinical symptoms being P&N, heat, autonmoic failure, sensory loss, areflexia

Pruritus

Nephrogenic Systemic Sclerosis

• ARF or CRF• Within 2 months of

exposure to G+• Severe pain, tightening,

burning of skin associated with redness and swelling.– Ultimately, joint

contractures and limited mobility

Gadolinium-based contrastagents are contraindicated in patients

on dialysis, and use of these agents with MRI in patients with a GFR < 30

mL/min should be avoided.

Treatment Related

• Dialysis dysequilibrium syndrome• Dialysis dementia• EPO-related• Rejection encephalopathy• Anti-rejection Rx related PRES

Treatment Related• “Dialysis dysequilibrium syndrome”

– Rapid clearance of BUN / other osmotically active solutes

• Nausea, vomiting, restlessness, cramps, confusion

– Easily avoided slowing rates of dialysis, using smaller dialysate volumes and more frequent sessions

• “Dialysis dementia”– Aluminum accumulation of GM

• Dysarthria, language disturbance, apraxia, personality, psychosis, myoclonus, seizures and dementia.

Now considered a “non-issue,” as modern day dialysis takes rates and contents of dialysate into account.

Nonetheless, errors do occur and should be cognizant of it.

Treatment Related• EPO-related (for CKD)

– 1/3 pt’s get HTN and can manifest with PRES– Careful monitoring of BP when initiating therapy and slow uptitration

of dose

• Anti-rejection Rx related – PRES and HTN // multifactorial BBB disruption, demyelination and

endothelial damage• Cyclosporine, tacrolimus

• Rejection encephalopathy– Within 3 months (up to 2 yrs) of transplantation– Cytokine induced (hypothesis)– Complete recovery after Tx rejection

Describe the findings

Dialysis patient who

became acutely

hypertensive post dialysis

A note about EPO

• Side effects as listed on product monograph:o >10% = HTN, headache, fevero 1-10% = DVT, edema, thrombosis

o Cardiovascular: Erythropoiesis-stimulating agents increase the risk of serious cardiovascular events, thromboembolic events, stroke, and mortality when administered to target Hgb levels >11 g/dL (and provide no additional benefit); a rapid rise in Hgb (>1 g/dL over 2 weeks) may also contribute to these risks.o CKD concerns; use the lowest dose sufficient to reduce the need for RBC transfusionso HTN / Cardiovascular concerns; decrease the epoetin dose if the hemoglobin increase

exceeds 1 g/dL in any 2-week period.

o Seizure concerns; increased risk in CKD, thus monitor upon initiation

Summary Renal NeurologyPractical Point

Name 2 potential etiologies for myelopathy in CRF patient?

1. Zinc (PO or IV) given thus causing a Cu deficient state

2. Acquisition of HTLV1 via blood transfusions during HD

3. Epidural hematoma (coagulopathic)4. SC infarct (vascular RF)

Practical Point

Clinical Exam Pearl

• Asterixis and myoclonus may be elicited with the hands outstretched, but may be more sensitively assessed by looking at the protruded tongue or the index finger raised with the palm placed on a firm surface

Practical Point

32F “African American”. Febrile illness culminating in seizure. R frontal lesion

identified and biopsied. Dx?

CASE 6

•Non-necrotizing granuloma•Giant cells•-ve stains for fungus or TB

Neurologic Manifestations of Systemic Inflammatory Disease(s)

Fundamentals of Sarcoid

• Dx of exclusion– Must r/o tuberculous, fungal, carcinomatous seeding

• Defined by histologic terms, thus mandates tissue Bx– Bx shows 3 cardinal features

1. Macrophage reaction with epitheloid histiocytic differentiaion of macs, without necrosis “non-caseating”

2. Multinucleated giant cells3. Lymphcytic of monocytic infiltration

• Must go the ‘whole 9 yards’, as sarcoidosis is treatable; potentially reversible

TNFTNFαα

Produced by WBC and endothelia in response to inflammation

Proinflammatory response

Produced by macrophages as well and auto-amplifies cascade

What % of Sarcoid Patients Develop Nervous System Involvement?

• Only 5% of sarcoid patients have neurologic involvement• Up to 35% of patients with NS can present with

only nervous system manifestations

• Isolated CNS sarcoid is exceedingly rare.

“Lofgren’s syndrome”

• “Acute” systemic phenotype (9 - 34% of patients)

– Arthritis– E. nodosum– Bilateral hilar

adenopathy

“Heerfordt’s SyndromeHeerfordt’s Syndrome”

• Parotid gland enlargement/Swelling

• Uveitis• Facial neuropathy (CN VII)• Fever

HIGHLY SUGGESTIVE OF HIGHLY SUGGESTIVE OF SARCOID!SARCOID!

Uveoparotid syndrome

Practical Point

Clinical Presentation; “protean”• Constitutional ++• Pulmonary; fibrosis, dysnpea • Ophthalmologic; uveitis, vitritis, retinal vasculitis• Dermatologic; e nodosum• CNS; see next slide• Cardiac; arrythmias• Hepatic; infiltration with variable impairment LFT• MSK; neuropathy, myopathy• Metabolic; hypercalcemia, calciuria

Practical Point

NeurosarcoidMayo Clinic Series [84 pt’s]

• Cranial nerve 65%• Myelopathy 18%• Cauda / Conus syndrome 3.5%• Polyradiculopathy 2.3%• Cerebellar 4.7%• Hemiparesis 2.3%• Myopathy 6%• H/A 25%• Encephalopathy 12%• HC 8.3%• Sz 8.3%• Hypothalamic / pituitary 17%• Chronic meningitis (h/a, encephalopathy, HC, sz or CN palsy with CSF pleocytosis;

no parenchymal pathology) 77%

NeurosarcoidMayo Clinic Series [84 pt’s]

• Cranial nerve 65%• Myelopathy 18%• Cauda / Conus syndrome 3.5%• Polyradiculopathy 2.3%• Cerebellar 4.7%• Hemiparesis 2.3%• Myopathy 6%• H/A 25%• Encephalopathy 12%• HC 8.3%• Sz 8.3%• Hypothalamic / pituitary 17%• Chronic pachymeningitis (h/a, encephalopathy, HC, sz or CN palsy with CSF

pleocytosis; no parenchymal pathology) 77%

Summary: Neurosarcoid

• Chronic pachymeningitis (h/a, encephalopathy, HC, sz or CN palsy with CSF pleocytosis; no parenchymal pathology) 77%

• Cranial nerve 65%– VII, VIII, II

• H/A 25%• Myelopathy 18%• Hypothalamic / pituitary 17%

Neurosarcoid; InvestigationNeurosarcoid; Investigation• Routine; Peripheral blood counts, Serum chemistries,

including creatinine and liver enzymes• ECG• Postero-anterior chest radiograph or CT chest• PFTs, including spirometry and DLCO• Tuberculin skin test, and negative stains on Bx

– Non-caseating granulomas on tissue bx

• ACE level (84% PPV, 74% NPV)• Urine calcium / serum calcium• BAL (CD4:CD8)

– reduced number of CD8 cells, an elevated CD4 to CD8 ratio, and an increased amount of activated T cells, CD4 cells, immunoglobulins, and IgG-secreting cells

• Routine ophthalmologic examination

Practical Point

CSF in Neurosarcoid

• Most sensitive biomarker is elevated CSF protein– I.e, normal protein argues strongly against the dx– Not specific

• Low glucose (variable); 15%• Pleocytosis common; 72%

– 0-455cells (mainly lymphs)

• OCB; 18%

ACE; setting the record straight

• May be helpful with routine chemistries– Secreted by sarcoidal granulomas

• Approximately 60% elevated in systemic disease

– Lacks sensitivity and specificity

• Not useful in CSF (sensitivity 24%)– False positive also very alarming (fungal meningitis,

carcinomatous)

• So, do not hang your hopes of the ACE level

MR features of neurosarcoidosis

• CNS intraparenchymal lesions of high T2 signal and G+ enhancement

• Pituitary / sella, leptomeningeal and nerve root (including cranial) with G+ enhancement

• Dural enhancement• Optic nerves• Basal meningitis +/- communicating

hydrocephalus

Neuro-Ophthalmologic Manifestations• 2nd most common system involved (next to

pulmonary)• Most frequently, the anterior segment is involved.

• Chronic granulomatous uveitis, • conjunctival granulomas, scleritis, episcleritis, and interstitial

keratitis.

• Posterior segment • Vitritis and periphlebitis

• it is sometimes the sole manifestation of ocular sarcoidosis but usually accompanies abnormalities in the anterior segment.

• Severe vasculitis associated with exudates gives the appearance of candle-wax drippings.

Neuro-Ophthalmologic Manifestations

• With chronic inflammation in the lacrimal system, the patient may develop keratoconjunctivitis sicca (secondary granulomas)

• Ophthalmopathy; Exactly mimics thyroid eye thyroid eye disease disease – Spares the tendon

C=anterior uveitis and synechiae

Enlarged nodular lacrimal gland

White, mutton-fat, granulomatous keratic precipitates

candle-wax drippings

Blind Bx of What Can be used to confirm non-caseating granulomas for CNS sarcoid?

• Lip/minor salivary gland• Rectum• Abdominal fat pad• Duodenum• Meninges• Conjunctiva

Practical Point

Blind Bx of What Can be used to confirm non-caseating granulomas for CNS sarcoid?

• Lip/minor salivary gland• Rectum• Abdominal fat pad• Duodenum• Meninges• Conjunctiva

Practical Point

Deciding on Therapy

• Tissue Dx 1st and foremost• Decide on biomarker that will be followed to

tailor therapy– CSF pleocytosis– MR enhancing lesions*

• May take months for G+ enhancement to disappear despite clinical response

– Neurologic clinical deficits

Therapy• Cornerstone is corticosteroids

– 3 induction options1. 1g IVMP qd x 5d, then oral pred 60 mg / day2. Pred 60mg/day or 1mg/kg3. Pred 60mg po qOD from onset

• Steroid sparing agents (many options)– No RTC evidence

• Neurosurgery• Cranial irradiation

Plan for a minimum of 6 months of therapyRelapse rate 10-30% in successfully treated patients

Cornerstone of therapyCornerstone of therapy

Treatment Options

Immunomodulators• Corticosteroids• Azathioprine• Methotrexate• Chlorambucil• Cyclophosphamide• Cyclosporine• Hydroxychloroquine*• Mycophenolate mofetil• Tacrolimus

TNF α blockers• Thalidomide• Pentoxyfylline• Infliximab*• Etanercept

DO NOT FORGETDO NOT FORGET•DEXA, calcium, Vit D, bisphosphanateDEXA, calcium, Vit D, bisphosphanate

•Septra 3X/wkSeptra 3X/wk•PPI or H2 blockerPPI or H2 blocker

•BP and CBGM checks in collaboration BP and CBGM checks in collaboration with GP / Internistwith GP / Internist

Name this test and most likely Dx

34F, 6 month Hx of patchy sensory phenomena over thighs, calves, forearms and nose.

Systems review reveals only complaints of dry mouth and eye (sicca); no other autonomic complaints

CASE 9

Sjögren Syndrome• Primary (50%) SS

• More severe sicca complex• Secondary (50%) SS

• RA, SLE, dermatomyositis, MCTD• Milder, slower progression

• Clinically; Sicca complex• Pathologically; lymphocytic

infiltration of exocrine glands• Neurological manifestation(s) can

sometimes be the first manifestation of the systemic disorder [1/3 present with ‘extraglandular’ manifestations]• Manifestations?Manifestations?

Xeropthalmia, xerostomia, keratoconjunctivitis sicca

Diagnostic criteria exist

• Beyond scope of this talk• Objective clinical findings with subjective sicca

complaints and histopathology– Serology; anti SSA (Ro) and anti SSB (La) [60%]– Schirmer’s Test– Rose Bengal for corneal abraisons– Parotid gland salivary production (nuclear med)– Minor salivary gland (lip) biopsy

Important exclusions: RTX, anti-chol Rx, HCV, AIDS, preexisting lymphoma, sarcoid, GVHD

Sjögren’s SyndromePrimarily PNS

CN V

The optimal management of peripheralnervous system complications of SS is unclear

(usual players involved IVMP, IVIG)Spontaneous improvement does occur

PNS CNS (poorly characterized)

MS mimic; clinical and paraclinical

Clinical Neurology

• Classic case:– severe loss of vibration and proprioception sensation, – pseudoathetosis in her fingers, – areflexia, – sensory ataxic gait– Romberg sign – Pupillary abnormalities (see below)– Autonomic neuropathy

• Adie’s tonic pupils (ciliary ganglionitis)

Sensory Wandering = PseudoathetosisSensory Wandering = Pseudoathetosishttp://www.nejm.org/doi/full/10.1056/NEJMicm0907786

Practical Point

For your interest onlyFor your interest only

Neuro-Sjogren’sNeuro-Sjogren’s• Sensory ataxic neuronopathy with autonomic involvement is highly

suggestive of SS. • Peripheral nervous system disease often precedes the clinical diagnosis of

SS. – Distal paresthesias, which may gradually spread more proximally, and loss of

JPS

• The MRI in patients with a sensory ataxia may show T2 hyperintensity in the cervical spinal cord. – Ganglioneuritis may be the cause of the sensory ataxic form of neuropathy

seen in SS

Ddx dorsal column hyperintensities

• B12 deficiency• DRG-opathy• Freidrich’s Ataxia• Cu Deficiency• Dorsalis Tabes• HIV vacuolar myelopathy

T2 hyperintensities in the dorsal columns is the neuroradiological correlate of degeneration of large myelinated sensory fibres due to damage to the dorsal root ganglion cells (as has been confirmed in pathological studies)

T2 hyperintensities therefore possibly reflects gliosis.

Clinical Clues to Ganglionopathy

• It may be difficult to distinguish numbness of small fiber sensory peripheral neuropathy from that of sensory ganglionopathy based just on clinical grounds.

• Aside from lower and upper extremity sensory impairment, the face may be affected (nose)

• EDX: reduced or absent SNAPs and normal (or near normal) CMAPs– Normal f-waves– Abnormal H-Reflexes

Can occur to small and large fibers

Note Association b/w SS and NMO

• Neuromyelitis optica can occur in association Neuromyelitis optica can occur in association with SSwith SS– Anti-SSA (Ro) frequently found in NMO patients

(with or without SS)– NMO-IgG prevalence same in SS pt’s without

NMO

• If diseases co-exist, treat NMO-spectrum disorder as if no SS– Generally involve IVMP, PLEX, azathioprine

Can you name a brief differential for selective sensory neuronopathy? (4)

Practical Point

Ddx primarily sensory, patchy, non-length dependent neuropathy

Ddx primarily sensory, patchy, non-length dependent neuropathy

1. Toxic neuronopathy (chemo = cisplatin, pyridoxine > 250-500mg /d)

2. Paraneoplastic sensory neuronopathy• SCLC; Anti-Hu Ab

3. Acute sensory neuronopathy syndrome• Post anti-biotic use [Flagyl]

4. Chronic idiopathic ataxic neuronopathy • ?unknown toxic exposure

5. Neuronopathy associated with SS6. Primary biliary cirhhosis related ganglionopathy /

neuropathy• Immune mediated

7. Sarcoidosis8. Gluten Enteropathy

48F with hands (shown) presents with a non-compressive foot drop.

• What’s the most likely Dx and pathophysiology?

CASE 10

32F with JRA presenting with acute tetraparesis after a fall, requiring

ventilatory support.

• What’s the most likely underlying pathophysiology?

CASE 11

Rhumatoid Arthritis (RA)Rhumatoid Arthritis (RA)

1. Systemic inflammatory disease characterized primarily by a polyarthritis due to chronic synovial tissue inflammation– Can progress to cartilage damage and bone

erosion– Spares the spine (C-spine exception)

2. Nervous system complications related to disease process itself or the therapies

Not DIP (OA)

4/7 necessary

2/3; not sensitive or specific

Practical Point

Neuro-RA• CNS

– Atlanto-axial instability; high cervical myelopathy with quadriparesis and respiratory failure

• Asymptomatic, neck pain and paresthesias, occipital headaches from C2

– Myelopathy may also result from compression by extradural rheumatoid nodules or by epidural lipomatosis (chronic steroid use)

– VBI from damage to vertebral a.’s– Rhumatoid meningitis (pachy or lepto)

and Rhuamtoid vasculitis (rare), Sz, dementia, hemiparesis, cranial nerve palsy, blindness, hemispheric dysfunction, cerebellar ataxia, or dysphasia, “NPH”

The joints between C1 (the atlas) and C2 (the axis)—particularly the space between the transverse atlantal ligament and the odontoid process, and the joint between the anterior atlas arch and the odontoid—are the most common sites of cervical involvement in RA

The joints between C1 (the atlas) and C2 (the axis)—particularly the space between the transverse atlantal ligament and the odontoid process, and the joint between the anterior atlas arch and the odontoid—are the most common sites of cervical involvement in RA

Destruction of articular facets of C2,resulting in descent of the skull and upward migration of the odontoid

Destruction of articular facets of C2,resulting in descent of the skull and upward migration of the odontoid

Gross destruction of the dens axis

Extensive pannus formation

Stepladder phenomenon

Surgical Indications

• Strong indications for surgery to reduce the subluxation and stabilize the spine include myelopathy (or brainstem compression from basilar invagination) and intractable pain or severe stenosis in conjunction with spinal instability (Kim and Hilibrand, 2005).

• Note:– Caution with intubations– Office maneuvers (such as Dix Hallpike)

Neuro-RA

• PNS– Entrapment neuropathies

– rheumatoid tenosynovitis, nodules or joint deformities

– Vasculitic Necrotizing Neuropathy (noncompressive)

– Neuropathy (axonal); DSPN (sensory)

– Mononeuritis multiplex Medium-sized epineurial blood vessel with fibrinoid necrosis of its wall and perivascular and transmural mononuclear cell infiltration

Median, post tib, une, enw, PIN (supinator and hypertrophied synovial tissue)

•Methotrexate is now one of the most commonly used DMARD in RA•Anti-malarials•Newer biologics

(?irreversible)

Practical Point

Methotrexate Toxicity; know it.

• Rare AE with oral, low-dose conventional Tx• Can get severe leukoencphalopathy with

higher dose IV or IT; especially if concomitant RTX– Malignancy treatment (i.e, ALL; Dana Farber

Protocol)• Don’t forget myelopathy

Practical Point

Methotrexate Leukoencephalopathy

Newer Biologics

• DMARD therapy failure• TNF-α inhibitors

– Infliximab (Remicade)– Etanercept (Enbrel)– Adalimumab (Humira)

Adverse EffectsAdverse Effects: – increased risk for systemic infection, lymphoma– reactivation of TB

CNS demyelination (R, H)CNS demyelination (R, H)Bilateral anterior toxic optic neuropathy (R)Bilateral anterior toxic optic neuropathy (R)

CIDP-like neuropathy (E)CIDP-like neuropathy (E)MMNCB (R)MMNCB (R)

AVOID IN PATIENTS WITH PAST HX of MS or other CNS DEMYELINATING

DISEASES

Almost done...

Name this important funduscopic finding.What immediate test(s) should you order next?

56M fever and left pronator drift.Swollen L ankle.ESR 274, CRP 300

Practical Point

Potential Future Topics• Neuro-Lupus• Electrolytes Disturbances in Neurology• Vascular complications of systemic diseases

– i.e, IE, SBE, cancer, hemoglobinopathies, APLAS and CAPS

• Neuro-Hematology– B12, TTP-HUS, ITP, homocysteine metabolism

• Neurooncology• “Myelopathies in cancer patients” or “stroke in cancer patients”• CNS/PNS complications of cancer• Complications of

– Rx, RTX, Surgery

• The paraneoplastic wonderland• Neurologic complications of pregnancy and delivery

Advice to R5’s; Writing The Quiz• Keep your cool when under fire• ABC’s• Dissect the case slowly, an ‘aha’ moment will

hopefully occur• CNS/PNS involvement if common pathologies, or

the most talked about presentations– No zebras on RCE (for the most part)

• Know your approach to hyponatremia and thrombocytopenia

• Do not be afraid to consult; know your limits

Practical Point(s)

Post-Test• Neurologic manifestations of celiac disease is primarily related to

specific vitamin deficiency state(s)• The CNS is the second most common system involved in sarcoid

(outside of pulmonary)• Most sensitive biomarker for neurosarcoid is CSF ACE level• Phenytoin is contraindicated in a liver failure patient• Name a purported biomarker that indicates active neuropsychiatric

SLE. • SS is one of the classic syndromes associated with sensory

neuronopathy• It is safe to use Remicade for RA in a patient with concomitant

RRMS

T/F

T/F

T/F

T/F

Anti-Ribosomal P (stay tuned for next talk)

T/F

T/F

References (reviews)

• Continuum; Neurologic Complications of Systemic Disease (access via VPN or AAN membership). Feb 2008, 2011

• The dorsal root ganglion under attack: the acquired sensory ganglionopathies. Pract Neurol 2010; 10: 326–334

• Intravenous thrombolysis in Sneddon’s syndrome. Case Reports / Journal of Clinical Neuroscience 19 (2012) 326–328

• Neurosarcoidosis: a clinical dilemma. Lancet Neurology. Neurology Vol 3 July 2004

• Metabolic Encephalopathies. Neurol Clin 29 (2011) 837–882• Robbins Pathology – Sarcoid pathophysiology• Bradley: NICP • Uptodate.com

• Curr Opin Neurol 2012, 25:306–315

SLESSSystemic SclerosisRABehcet