survey of neurology eric kraus, md wapa 1/26/13. ars question a 48 y.o. male presents with gradual...
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Survey of Neurology
Eric Kraus, MD
WAPA
1/26/13
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ARS Question
A 48 y.o. male presents with gradual progressive weakness of his proximal legs and arms without sensory loss. The exam confirms the weakness, reflexes are reduced, and no fasciculations are seen.
The best anatomical localization is?
A. BrainB. MuscleC. Motor neuronD. Spinal cordE. Peripheral nerve
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ARS Question
A 26 y.o. female presents with subacute weakness of her legs, bladder urgency, and sensory loss in the legs. Arms, speech and swallow are fine. The exam confirms the weakness, leg reflexes are increased, and a T10 sensory level is present.
The best anatomical localization is?
A. BrainB. MuscleC. Motor neuronD. Spinal cordE. Peripheral nerve
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Neurological “Levels”
Brain Brainstem Spinal cord Motor neuron Peripheral nerve Neuromuscular
junction Muscle
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
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Often unilateral Motor and/or sensory Language Consciousness Memory Behavior Vision Seizures Movement d/o
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
Level: Brain
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Often unilateral Motor and/or sensory Consciousness Cerebellar Movement d/o Cranial nerves
» Diplopia
» Vertigo
» Face
» Swallow
» Tongue
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
Level: Brainstem
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Often bilateral Motor and/or sensory Head OK Bowel, bladder and
erectile
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
Level: Spinal Cord
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Asymmetric bilateral Motor Proximal and distal Insidious onset Fasciculations
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
Level: Motor Neuron
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Symmetric or focal Sensory > motor Cranial nerves 3-12 Often distal
» Stocking-glove
If proximal think» Demyelinating (UE + LE)» Cauda equina (LE)
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
Level: Peripheral Nerve
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Asymmetric bilateral Motor only Proximal and distal
» Eyes involved in myasthenia gravis
Fatigable weakness» Myasthenia gravis
Progressive weakness» Lambert-Eaton
myasthenic syndrome
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
Level: NMJ
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Level: Muscle
Symmetric bilateral Motor only Usually proximal
UPPER MOTOR NEURON
LOWER MOTOR NEURON
MUSCLE
SENSORY NERVE
BRAIN
BRAINSTEM
SPINAL CORD
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ARS Question
This is a 22 yo woman with sensory loss in the right hand that spread to her right trunk and leg over 2 weeks. No weakness. Last year she had numbness in her left face for 4 weeks. Her exam reveals the sensory loss to pinprick. What test is likely to confirm your diagnostic suspicion?
A. Brain MRIB. Spinal fluid evaluationC. Lumbar MRID. Electrodiagnostic testingE. Tibial evoked potentials
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Multiple Sclerosis
CNS disease Primarily demyelinating
» Axonal loss is also present
Females/white > males/non-white Sex 2-3:1 = F:M Prevalence 5-250/100,000 population Associated with Vit D deficiency and EBV
exposure
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MS: Types
Relapsing-remitting MS (RRMS)» 60-80%» Secondary progressive» Progressive relapsing
Primary progressive MS (PPMS)» 20-30%» Older, cervical disease
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MS: Clinical
Optic neuritis» Blurry, color desaturation» Painful eye movement
Weakness, spasticity Sensory
» most common initial presentation
Ataxia, tremor Cognitive
Lhermitte’s sign Fatigue Heat and exercise
intolerance Bladder Sexual dysfunction
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RRMS: Clinical
Exacerbations over hours to days» > 24 hrs.
Resolution over days to months 2 events separated in time and space
» Time: one month» Space: clinical or paraclinical (MRI, CSF, EPs)
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PPMS: Clinical
Chronic symptoms > 6 months No other explanation Testing positive
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MS: Testing
MRI CSF (Oligoclonal bands) Evoked potentials
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MRI
90-95% sensitive at first presentation
Visual detection of plaques» Demyelination» Gliosis» Inflammation
Location» Periventricular» Corpus callosum» Cerebellum» Brain stem
Acute lesions enhance (Gd+)
MacDonald Criteria
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MRIMRI
Axial flair Coronal T1 with Gad Sagittal flair
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CSF
Detects immune changes inside the blood-brain barrier
Oligoclonal bands» Sensitivity
– 85-90% RRMS– 60% PPMS
» Specificity 60%
Elevated IgG index Normal glucose Protein <100 Cells <50
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Evoked Potentials
Detects conduction slowing through CNS» Demyelination
Type : Sensitivity» Visual : 70%» Tibial : 70%» Median : 60%
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MS: Treatment
Symptomatic Acute
» Methylprednisolone 1000mg IV qd x 3-5 Chronic (Disease modifying drugs)
» Interferon beta-1b (Betaseron)
» Interferon beta-1a (Avonex)
» Interferon beta-1a (Rebif)
» Glatiramir acetate (Copaxone)
» Nataluzimab (Tysabri)
» Fingolimod: oral, new 2011 Mitoxantrone (worsening RRMS and SPMS)
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Pathophysiology
Lymph Node Blood Vessel Brain
Neuron
Myelin
AxonBlood-Brain Barrier
VLA-4
Myelin Basic Protein
T-Cell
Maturation S1P1
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Treatment: Methylprednisone
Lymph Node Blood Vessel Brain
Neuron
Myelin
AxonBlood-Brain Barrier
VLA-4
Myelin Basic Protein
T-Cell
Maturation S1P1 XXX
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Treatment: Beta-interferons
Lymph Node Blood Vessel Brain
Neuron
Myelin
AxonBlood-Brain Barrier
VLA-4
Myelin Basic Protein
T-Cell
Maturation S1P1
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Treatment: Copaxone
Lymph Node Blood Vessel Brain
Neuron
Myelin
AxonBlood-Brain Barrier
VLA-4
Myelin Basic Protein
T-Cell
Maturation S1P1
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Treatment: Tysabri
Lymph Node Blood Vessel Brain
Neuron
Myelin
AxonBlood-Brain Barrier
VLA-4
Myelin Basic Protein
T-Cell
Maturation S1P1
X
X
X
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Treatment: Fingolimod
Lymph Node Blood Vessel Brain
Neuron
Myelin
AxonBlood-Brain Barrier
VLA-4
Myelin Basic Protein
T-Cell
Maturation S1P1X
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ARS Question
A 56 y.o. man presents with trouble walking, small hand writing, and a resting tremor.
You make a presumptive diagnosis and suggest:
A. Sinemet trialB. Head MRIC. Propranolol for essential tremorD. Stroke work-up
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Parkinson’s Disease
Loss of dopaminergic neurons in the substantia nigra
Lewy bodies Differentiate from broader classification
of parkinsonism Mean age of onset 55yo
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Parkinsonism
Parkinson’s Disease Neuroleptic side effect Post-encephalitic Toxins (Mn, CO, MPTP) Dementia Wilson’s disease Basal ganglia
calcifications
Parkinson-plus syndromes» Progressive supranuclear
palsy» Corticobasoganglionic
degeneration» Multisystem atrophy
– Autonomic
– Cerebellar
» Diffuse Lewy body disease
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PD: Clinical
Slow progressive course 4 cardinal features
» Resting tremor» Bradykinesia» Rigidity (cogwheel)» Postural reflex impairment
Other: dementia, depression, autonomic
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PD: Treatment
Sinemet = carbidopa/levodopa» Levodopa converts to dopamine
» Most potent drug for PD Dopamine agonists
» Act directly on dopamine receptors
» Synergy with levodopa
» Ex. Pramipexole, Ropinirole COMT inhibitors
» Block COMT metabolism of levodopa to DA
» Ex. Entacapone Other
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Levodopa
3-OMD Dopamine
COMT AADC
Levodopa
3-OMD
AADC COMT
Dopamine
Homovanillic acid
3,4-DHPA 3-MT
COMT
COMT
MAO-B
MAO-BCOMT = catechol-O-methyltransferaseAADC = amino acid decarboxylaseMAO = monoamine oxidaseOMD = O-methyldopaDHPA = dihydroxyphenylacetic acidMT = methoxytyramine
Treatment Flow Chart
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ARS Question
A 32 y.o. male feels dizzy several times a day when he moves his head to the left. He describes a spinning sensation that lasts 1 minute. The exam reveals nystagmus with head maneuvers.
Q. Categorize - treatment?
A. Presyncope - ValiumB. Vertigo - ValiumC. Dysequilibrium - Physical therapyD. Dysequilibrium - MeclizineE. Vertigo - Otolith repositioning
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Benign Positional Vertigo
Etiologies» Head injury» Viral» Idiopathic
Canalolithiasis» Calcium deposit in a
semicircular canal» 90% posterior canal
Clinical» Positional vertigo» Positional nystagmus
– Hallpike maneuver
Treatment» Epley maneuver
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Utricle and Otoliths
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Cupula
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Left Posterior Canal BPV
Hallpike maneuver
Nystagmus: Geotropic torsional Upbeat
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ARS Question
A 27 year-old male complains of dizziness starting 3 hours ago that is becoming more severe. He describes a constant spinning. Your exam is remarkable for hearing loss to finger rub in the left ear and horizontal nystagmus to the right no matter which way he looks.
A. Acute vestibular syndromeB. Benign positional vertigoC. Meniere’s diseaseD. Central vertigo (e.g. stroke, MS)
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Acute Vestibular Syndrome
Vestibular neuritis» Without auditory
symptoms Labyrinthitis
» With auditory symptoms Clinical
» Sudden onset» Constant» Unidirectional nystagmus» Fixation helps» Days to weeks
Viral?» Valacyclovir* not helpful
Treatment» Steroids* acutely
– Prednisone 120mg qd with 3 wk taper
» Valium» Scopolamine» Anti-emetics
*Strupp, et. al. NEJM 2004;351:354
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ARS Question
This 58 year-old man first noticed right hand weakness 4 months ago. Three months ago he developed dysarthria and mild trouble swallowing liquids. One month ago he developed left hand weakness. All the symptoms are progressing. Twitching is present. No pain or sensory loss.
You make a presumptive diagnosis and order what test?
A. B12 levelB. Electrodiagnostic test (EMG)C. Brain MRID. TSHE. CSF for increased protein
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ALS: Clinical
Upper motor neuron» Weakness» Increased reflexes» Spasticity» Pseudobulbar» Babinski sign
Lower motor neuron» Weakness» Decreased reflexes» Atrophy» Fasciculations» EMG denervation
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ALS: Treatment
Rehabilitative Medications
» Riluzole» Symptomatic
Gastrostomy tube Mechanical ventilation
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ARS Question
This 64 year-old man began having burning pain in his toes 3 years ago. Slowly, it has moved to the knee. The hands became dysesthetic 1 year ago. Weakness is also present in the feet and he is off balance when walking. Reflexes intact except at the ankles.
What is the most likely etiology?A. VasculitisB. Guillain-Barre syndromeC. Diabetes mellitusD. B12 deficiency
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ARS Question
This 24 year-old man began having tingling in his toes 3 days ago. Rapidly, it has moved to the whole body accompanied by weakness such that he can’t get out of bed and is having trouble breathing and swallowing. Reflexes are absent.
What is the most likely etiology?A. VasculitisB. Guillain-Barre syndromeC. Diabetes mellitusD. B12 deficiency
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Peripheral Neuropathy
Step 1: History and physical Step 2: Electrodiagnostics Step 3: Putting it all together
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Step 1: History and Physical
True peripheral nerve disorder?» Cervical stenosis» Fibromyalgia» MS (central)» Myopathy» ALS
Clinical» Usually sensory >
motor
Description» Burning» Stabbing» Allodynia» Numb» Cold
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Describe Features
Distribution» Length-dependent» Proximal and distal
– Think demyelinating
Acute vs. chronic
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Step 2: Electrodiagnostics
Upsides» Confirm neuropathy» Physiology
– Axonal vs. demyelinating
Downsides» Pain» Cost» Time» Miss small fiber dis.
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Step 3: Putting It All Together
Is a neuropathy confirmed? Work-up based on characteristics Diabetes mellitus is most common Unknown also very common Biopsy usually not helpful
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Differential: Demyelinating
Guillain-Barre syndrome (AIDP)
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
CIDP variants Diphtheria N-hexane Acute arsenic
Paraproteinemic (monoclonal gammopathy)» MGUS
» Multiple myeloma
» Waldenstrom
» POEMS
» Cryoglobulinemia Inherited
» Charcot-Marie-Tooth type 1
» Metachromatic leukodystrophy
» Krabbe
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Differential: Large Fiber Axonal
Diabetes mellitus* Paraproteinemic* Paraneoplastic Uremia Vasculitis B12 deficiency* Vit E deficiency Hypothyroid
Porphyria Sarcoid Toxins
» Chemotherapy» Pyridoxine» Nitrous oxide» Lead» Mercury
Inherited» Charcot-Marie-Tooth type 2
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Differential: Small Fiber Axonal
Diabetes mellitus Paraproteinemic
» Amyloidosis
Paraneoplastic Cryoglobulinemic
» Hepatitis C
HIV Leprosy
Fabry disease Toxins
» Chemotherapy» Thallium
Inherited» Hereditary sensory
autonomic neuropathy
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Differential: Mononeuropathy Multiplex
Diabetes mellitus Vasculitidies
» PAN» Churg-Strauss» Wegener
Infection» Leprosy» Lyme» HIV
Connective tissue» RA» SLE» Sjogren
Inflammatory» Sarcoid
Cryoglobulinemia
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Mononeuropathy Multiplex Cont.
Amyloid Hereditary
» Hereditary neuropathy with liability to pressure palsy (HNLPP)
Neoplastic» Compression» Invasion» Paraneoplastic
Trauma Radiation Auto-immune
» Multifocal motor neuropathy with conduction block (MMN)
» Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)
» Multifocal acquired motor axonopathy (MAMA)
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Differential: Medications
Amiodorone (A/D) Perhexiline (A/D) Chloroquine (D) Vinca Alkaloids (A) Cisplatin (A) Paclitaxel (A) ddC, d4T, ddI (A) Dapsone (A) Isoniazid (A) Ethambutol (A)
Nitrofurantoin (A) Metronidazole (A) Chloramphenicol ? Phenytoin (A) Pyridoxine (A) Tacrolimus (D) Colchicine (A) Disulfarim (A/D) Procainamide (D Sulfasalazine (A) Thalidomide (A)
Drug Safety 29(1):23-30, 2006
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Diabetic Neuropathy
Symmetric» Distal sensory» Autonomic» Proximal lower limb» Acute cachectic» Treatment induced
Focal» Cranial nerve
– Pupil sparing 3rd
» Mononeuropathy– Limb– Trunk
» Proximal lower limb
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AAN Consensus
Conclusion: Patients with distal symmetric sensory polyneuropathy have a relatively high prevalence of diabetes or pre-diabetes (impaired glucose tolerance), which can be documented by blood glucose, or GTT (Class III).
Recommendation: When routine blood glucose testing is not clearly abnormal, other tests for pre-diabetes (impaired glucose tolerance) such as a GTT may be considered in patients with distal symmetric sensory polyneuropathy, especially if it is accompanied by pain (Level C).
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First Line Testing for Distal Sensory Neuropathy
Fasting plasma glucose» Impaired fasting glucose: 100-125mg/dl» Diabetes: >125mg/dl on 2 occasions
If fasting glucose okay, consider OGTT» Impaired glucose tolerance: 2hr post prandial glucose 140-
200mg/dl» Diabetes: 2hr post prandial glucose >200mg/dl
B12, SPEP
JD England, et.al. Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory, genetic, and autonomic testing; nerve biopsy; and skin biopsy (an evidence-based review). Neurology 2009;72:185
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Treatment
CE Argoff, et. al. Consensus Guidelines: Treatment Planning and Options. Mayo Clin. Proc. 2006; 81(4, suppl): S12-S25
DPN = Diabetic peripheral neuropathy
Tier 1 2+ RCTs in DPN Duloxetine, Pregabalin,TCAs, Oxycodone CR
Tier 2 1RCT in DPN Carbamazepine, Gabapentin,1+ RCT non-DPN Lamotrigine, Tramadol,
Venlafaxine
Topicals Capsaicin, Lidocaine
Other 1+ RCT non-DPN Buproprion, SSRI, PhenytoinMethadone, Topiramate
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Treatment
V Bril, et. al. Evidence-based guideline: Treatment of painful diabetic neuropathy. Neurology. 2011; 76:1758
RecommendationLevel A 2+ class 1 studies Pregabalin
Level B 1 class 1 study or Gabapentin, Sodium valproate2 class 2 studies Duloxetine, Venlafaxine,
Amitriptyline, Tramadol, Opiates, Capsaicin, TENS
Level U No class 1-3 studies Topiramate, SSRI, nortriptyline,Insufficient evidence Lidocaine, Alpha lipoic acid
Not helpful Evidence against Lamotrigine, Oxcarbazepine, Lacosamide, Mexilitine, Laser
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ARS Question
This 38 year-old man has SOB, trouble smiling and chewing, and mild proximal arm weakness. Both diplopia and ptosis are present. The symptoms are better in the morning and after rest. They are worse when reading, walking, and lifting.
Which two tests will help confirm your diagnosis?
A. CPK and brain MRIB. Repetitive nerve stimulation and CPKC. Repetitive nerve stimulation and brain MRID. Ach Rec Abs and brain MRIE. Repetitive nerve stimulation and Ach Rec Abs
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Myasthenia Gravis
Definition: autoimmune disease of the neuromuscular junction characterized by fatigable weakness
Antibodies against multiple epitopes on the muscle side
Failure to generate a muscle action potential
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Myasthenia Gravis
50-125/million Bimodal incidence
» Female 2nd-3rd decade
» Male 6th-7th decade
Types» Generalized 85%» Ocular 15%» Neonatal
– Abs from mother
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Neuromuscular Junction
Ach release Attach to Ach receptors Muscle contraction Ach detaches Acetylcholinesterase
Antibodies:» Ach receptor 85%» MuSK 7%» Unknown 8%
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Myasthenia Gravis
Clinical» Fatigability» Ptosis and diplopia» Sensory normal» Reflexes maintained» Bedside maneuvers
Diagnosis» H&P» Repetitive stimulation» Antibodies» Tensilon test» Chest imaging
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Myasthenia Gravis
Treatment» Thymectomy (not MuSK)» Anticholinesterase agents» Immunosuppression» Immunomodulation (plasmapheresis, IVIG)
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ARS Question
This 52 year-old male has painless weakness of his thighs and hands. On exam he can’t pinch, get out of the chair w/o pushing, and has absent knee DTRs. The CPK is 426 (2x normal). A muscle biopsy is likely to show which disease?
A. PolymyositisB. DermatomyositisC. Inclusion-body myositisD. Becker muscular dystrophyE. McArdle disease
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Myopathy
Inflammatory myopathy Muscular dystrophy Metabolic myopathies Other
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Myopathy
Inflammatory myopathy
Muscular dystrophy Metabolic myopathies Other
Polymyositis (PM)» Prox muscles and neck» CPK 5-10x normal
Dermatomyositis (DM)» Prox muscles and neck» Skin changes» CPK 2-10x normal
Inclusion body myositis (IBM)» Distal forearm, prox thigh» Most common after 50» CPK 1-5x normal
Biopsy
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Myopathy
Inflammatory myopathy
Muscular dystrophy
Metabolic myopathies Other
Inherited Progressive weakness and
atrophy» Variable distribution
Biopsy and DNA testing CPK normal to 100x No specific treatment yet
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A. Duchenne/Becker dystrophinopathy
B. Emery-Dreifuss
C. Limb-girdle
D. Facioscapulohumeral
E. Distal (myotonic dystrophy also involves the face)
F. Oculopharyngeal
Emery A. The muscular dystrophies. 2002. Lancet. 359:687-695.
Weakness Patterns in Different Weakness Patterns in Different Types of DystrophyTypes of Dystrophy
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Case: Muscular Dystrophy
This is a 18 year-old female who has had progressive weakness since the age of 15. It is both distal and proximal. No sensory loss is reported. Multiple immunosuppressive drugs have not worked. CPK 20,000.
Exam: Strength 4/5 (using wheelchair)Reflexes are reducedSensory normal
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Myopathy
Inflammatory myopathy Muscular dystrophy
Metabolic myopathies
Other
Glycolysis defect» Ex. McArdle’s disease
Fatty acid defect» Ex. Carnitine palmitoyl
transferase II deficiency Mitochondrial cytopathy
» Ex. Kearns-Sayer CPK increases when
metabolic system is stressed Myoglobinuria Biopsy and DNA testing
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Case: Metabolic Myopathy
This is a 18 year-old male who gets weak and has cramping after moderate exercise. Myoglobinuria has been noticed on two occasions. No sensory loss is reported. CPK 343.
Exam: Strength normalReflexes are presentSensory normal
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Myopathy
Inflammatory myopathy Muscular dystrophy Metabolic myopathies
Other
Drug-induced» Steroids» Statins
Infectious Sarcoid Amyloid Paraneoplastic Critical illness GVHD
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END