Neurologic Complications of
Systemic Disease
October 3rd 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
• 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” medicineNonetheless
should
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complicationsimportant
in neurologicand
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nothave
ignore...part
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objectives;
– Should
been covered inof
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refer to
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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
Outline
1. Neurologic Complications of Hepatic Failure
–
Hepatic encephalopathy, cirhosis and ALF
2. Alcohol and the nervous system
3. Neurogastroenterology
–
Mini-review of a few ultra-precise topics
4. Neurologic Complications of Renal Failure
5. Systemic Inflammatory Diseases
–
–
–
–
Sarcoid
Sjögren’s Syndrome
RA
SLE
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.
2.
3.
4.
5.
Asterixis
Bradykinesia
Dysarthria
Seizures
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.
2.
3.
4.
5.
Asterixis
Bradykinesia
Dysarthria
Seizures
Somnolence
Neurologic Manifestations of
Hepatic Failure / ALF
Clinical Clues
• Background
knowledge of
stigmata of chronic
liver disease may
help when
diagnosis is
ambiguous
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
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)
Pallidal hyperintensities on T1
Reflects a significant portosystemic shunt, NOT hepatic
encephalopathy
Mn deposition (reduced
excretion in bile)
90% of patients
Hypoglycemic Coma MR
DWI is key sequence
NB. Study excluded cardiac /
respiratory arrest
AJNR Am J Neuroradiology May 2012
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
Hepatic Failure / Disease
Grade II
•Asterixis
•Brady
•Rigidity
•Tremor
•Cerebellar
dysarthria
•Ataxia
II
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”
Practical Point
Principals of Management of Hepatic
Encephalopathy (acute and chronic)
1. Look for source (occult bleed)
2. Low protein in diet
3. Lactulose PO or enema; titrate to 3+ soft BM per
day
4. 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)
CASE 1.5
36 F overdose on acetaminophen
Describe
the
pertinent
findings.
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 (145155mmol/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)
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
Brain (1998), 121, 127–133
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”
CASE 2
Accompanying MR Brain
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
Practical Point
Wernike’s in Pregnancy
Note Ddx
Molar
pregnancy
HyperT4
Hepatitis
• 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
Neurologic Manifestations of GI
Disease
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
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 or 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 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
Perivascular inflammatroy
infiltrate
Perivascular Tg
Serum from patients with
gluten ataxia reacts with Purkinje
cell epitopes
Purkinje loss
Practical Point
Name 5 auto-immune or immune mediated
diseases (systemic or nervous system)
1.
2.
3.
4.
5.
MG
MS / ADEM
GBS
Dermatomyositis / polymyositis
Devic’s disease (neuromyelitis
optica)
6. Neuropsychiatric lupus
7. Rhumatoid arthritis
8. Sleroderma
9. Sjogren
10. Paraneoplastic syndromes +++
(NMDA-R encephalitis, SPS)
11. Thyroid eye disease (Graves) or
Hashimotos’ (SREAT)
1.
2.
3.
4.
5.
Vitiligo
DM1
Psoriasis
Celiac disease (ataxia,
neuropathy)
IBD
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
Describe the most pertinent findings...
Neurologic Manifestations of
ETOH Toxicity
ETOH and
the nervous
system
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...
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%
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
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
Normal neuroimaging (not shown)
– Bilateral asterixis
– Labs: Creat 864 umol/L, K 5.1, Hb 82
What is the next most important test
in this patient’s management?
Important to differentiate NCS from Uremic Encephalopathy;
very different treatments...
Neurologic Complications
1. Manifestations of uremic state
2. 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 fistulathrombosis (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 posttransplant
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
<25ml/min (myopathy)
Features
Uremic myopathy
possible
Parallels decline in renal
function
Clinical
“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+Gadolinium-based contrast
agents are contraindicated in patients
• Severe pain, tightening,
on dialysis, and use of these agents
burning of with
skin MRI in patients with a GFR < 30
associated withmL/min
redness
should be avoided.
and swelling.
– Ultimately, joint
contractures and limited
mobility
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 Now considered a “non-issue,” as
modern
dayrestlessness,
dialysis takescramps,
rates and
• Nausea,
vomiting,
confusion
contents of dialysate into account.
– Easily avoided slowing rates of dialysis, using
smaller dialysate
volumes
moreand
frequent
Nonetheless,
errorsand
do occur
sessions
should be cognizant of it.
• “Dialysis dementia”
– Aluminum accumulation of GM
• Dysarthria, language disturbance, apraxia, personality,
psychosis, myoclonus, seizures and dementia.
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
Dialysis
patient who
became
acutely
hypertensive
post dialysis
Describe
the findings
A note about EPO
• Side effects as listed on product monograph:
o >10% = HTN, headache, fever
o 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 transfusions
o 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
Practical Point
Summary Renal Neurology
Practical 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
CASE 6
32F “African American”. Febrile illness
culminating in seizure. R frontal lesion
identified and biopsied. Dx?
•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.
2.
3.
Macrophage reaction with epitheloid histiocytic differentiaion of
macs, without necrosis “non-caseating”
Multinucleated giant cells
Lymphcytic of monocytic infiltration
• Must go the ‘whole 9 yards’, as sarcoidosis is
treatable; potentially reversible
TNFα
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
Practical Point
“Heerfordt’s Syndrome”
Uveoparotid syndrome
• Parotid gland
enlargement/Swelling
• Uveitis
• Facial neuropathy (CN VII)
• Fever
HIGHLY SUGGESTIVE OF
SARCOID!
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
Neurosarcoid
Mayo 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%
Neurosarcoid
Mayo 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%
Practical Point
Neurosarcoid; 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
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
disease
– Spares the tendon
C=anterior uveitis and synechiae
Enlarged nodular lacrimal gland
White, mutton-fat, granulomatous keratic
precipitates
candle-wax drippings
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
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
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 options
1. 1g IVMP qd x 5d, then oral pred 60 mg / day
2. Pred 60mg/day or 1mg/kg
3. 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 therapy
Relapse rate 10-30% in successfully treated patients
Cornerstone of
therapy
Treatment Options
Immunomodulators
• Corticosteroids
• Azathioprine
• Methotrexate
• Chlorambucil
• Cyclophosphamide
• Cyclosporine
• Hydroxychloroquine*
• Mycophenolate mofetil
• Tacrolimus
TNF α blockers
• Thalidomide
• Pentoxyfylline
• Infliximab*
• Etanercept
DO NOT FORGET
•DEXA, calcium, Vit D, bisphosphanate
•Septra 3X/wk
•PPI or H2 blocker
•BP and CBGM checks in collaboration
with GP / Internist
CASE 9
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
Xeropthalmia, xerostomia,
keratoconjunctivitis sicca
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?
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 Syndrome
Primarily PNS
PNS
CNS (poorly characterized)
CN V
MS mimic; clinical
and paraclinical
The optimal management of peripheral
nervous system complications of SS is unclear
(usual players involved IVMP, IVIG)
Spontaneous improvement does occur
Practical Point
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 = Pseudoathetosis
http://www.nejm.org/doi/full/10.1056/NEJMicm0907786
For your interest only
Neuro-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
Can occur to small and large fibers
• 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
Note Association b/w SS and NMO
• Neuromyelitis optica can occur in association
with 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
Practical Point
Can you name a brief differential for
selective sensory neuronopathy? (4)
Ddx primarily sensory, patchy, nonlength dependent neuropathy
1. Toxic neuronopathy (chemo = cisplatin, pyridoxine > 250500mg /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 SS
6. Primary biliary cirhhosis related ganglionopathy /
neuropathy
•
Immune mediated
7. Sarcoidosis
8. Gluten Enteropathy
CASE 10
48F with hands (shown) presents
with a non-compressive foot drop.
• What’s the most likely Dx and pathophysiology?
CASE 11
32F with JRA presenting with acute
tetraparesis after a fall, requiring
ventilatory support.
• What’s the most likely underlying
pathophysiology?
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
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
Median, post tib, une,
enw, PIN (supinator and
hypertrophied synovial
tissue)
• 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
Practical Point
(?irreversible)
•Methotrexate is now one of the most commonly used DMARD in RA
•Anti-malarials
•Newer biologics
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
Methotrexate
Leukoencephalopathy
Newer Biologics
• DMARD therapy failure
• TNF-α inhibitors
– Infliximab (Remicade)
– Etanercept (Enbrel)
– Adalimumab (Humira)
AVOID IN PATIENTS WITH
PAST HX of MS or other
Adverse Effects:
CNS DEMYELINATING
– increased risk for systemic infection,
DISEASES
lymphoma
– reactivation of TB
CNS demyelination (R, H)
Bilateral anterior toxic optic neuropathy (R)
CIDP-like neuropathy (E)
MMNCB (R)
Almost done...
56M fever and left pronator drift.
Swollen L ankle.
ESR 274, CRP 300
Practical Point
Name this important funduscopic finding.
What immediate test(s) should you order next?
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
Practical Point(s)
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
Post-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. Anti-Ribosomal P (stay tuned for next talk)
• 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
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
SLE
SS
Systemic Sclerosis
RA
Behcet