Transcript Atropine Ophthalmic Administration Unmasking Undiagnosed

Charcot-Marie-Tooth
Prevalence:1/2500
type1:begins in first or second decade
manifestations: a ;slowly progressive weakness
b ; muscular wasting
c ; sensory impairment (legs)
d ; foot deformities
e ; upper limbs lnvolved later
2/3 cases
f;
pes cavus and hammer toes 75%
g;
mild kyphosis 10%
h;
hypertrophic peripheral nerves 25%
I;
absent ankle reflex (always)
j;
distal sensory impairment (vib-light T)
k;
essential tremor in hands (Rousy-Levy)
l ;
asymptomatic slowing NCV 10%
m ;exacerbate in pregnancy (1/3 temporary)
n ;routin tests normal
o ;CSF normal D D with CIDP
p ;sural biopsy onion bulb formation
q ;MNCV decrease >25%of normal lower
limit .NCV<38m/s in median N
r ;SNCV abnormal
CMT type 2 :1/3 cases –autosomal D
Symptoms: begin later- second decade
upper limbs involvement & tremor and
areflexia are less frequent
MNCV normal or mild abnormal
SNAP absent
Sural biopsy :hallmark axonal D
CMT X: similar to type 1
affected male more severely
no male to male transmission
second most common (7-16%)
associated with CNS involvement
(white matter)+ BAER abnormality
deafness
Ataxia ,dysarthria ,and
weakness after visiting high altitudes
CMT X : NCV in men significant slowing
BAER often abnormal
Biopsy axonal loss & demyelination
CMT 3 : Dejerine Sottas disease ;CSF pro
Progressive hyperthrophic neuropathy
Childhood onset- uncommon –areflexia
Proximal weakness-enlarged nerves
Sporadic(AR some times)-MCV<10m/s
CMT4: AR- childhood - progressive weakness
Inability to walking (adolescence)
NCV 20-30m/s
CSF pro is normal
Nerve biopsy : loss of myelination
onion bulb
DIABETIC NEUROPATHY
5% PER YEARS
RETINOPATHY-NEPHROPATHYNEURDPATHY
IDDM- NIDDM VULNERABLE TO D N
LEADING CAUSE OF PERIPHERAL
NEUROPATHY
FEREQUENCY OF D N 7-80%
RISK OF DEVELOPING SYMPTOMIC D N
5YEARS:4-10%
25YEARS:15%
66% HAVE OBJECTIVE D N
IDDM 15%--- NIDDM 13% SYMPTOMATIC
AGE&D M CORRELATE WITH ABNORMAL
VIBRATION TEST
HIGHER PERCENTAGE IN THOSE WITH LOW
SERUM INSULINE CONCENTRATION
RISK FACTORS WITH ON INCREASED
FOOT SENSATION :POOR GLYCEMIC
CONTROL-HEIGHT-AGE-ALCOHOL
EMG&NCV DEMONSTRATE SUBCLINICAL
ABNORMALITIES IN MOST PATIENTS WITH
IDDM AFTER5-10YEARS D N
CLASSIFICATION :SYMMETRIC
FOCAL
CLINICAL FEATURES
DYSTAL SYMMETRICAL P N
MOST COMMON D N
75% OF ALL D N
SENSORY LOSS&AUTONOMIC SYMPTOMS
CORRELATE WITH SEVERITY
MOST PATIENTS HAVE MINOR MOTOR SIGN
STOCKING&GLOVE DISTRIBUTION
BEGIN IN THE TOES
IN MORE ADVANCED CASES ANTERIOR
CHEST&ABDOMEN ARE AFFECTED
DYEING BACK PROCESS
LARGE FIBER-------SMALL FIBER
LARGE FIBER D N
PAINLESS PARESTHESIAS(TOE&FEET)
IMPAIRMENT OF VIBRATION&POSITION
DTR-ATAXIA SENSORY LOSS
DIABETIC POLYRADICULONEUROPATHY
ONSET DISTAL SYMMETRIC THEN PROXIMAL
SEGMENT
L SR00TS-THORACIC—CERVICAL
E M G –LOW GRADE ACTIVE
DENERVATION(THORACIC)
TRIGEMINAL BLINK REFLEX IS SPARED
DIABETIC POLYRADICULOPATHY
NORMAL S N C V—ROOT LEVEL IS
AFFECTED(EMG&CLINICAL)
NIDDM&IDDM ARE ASSOCIATED WITH
CIDP ------RESPONSE TO IVIG
SMALL FIBER D N
DEEP PAIN BURNING-ACHING-SHOOTING
ALLODYNIA TEMPERATURE&PAIN ARE
IMPAIRED—PERSERVATION OF DEEP
SENSE&DTR—AUTONOMIC
HYPERGLYCEMIC D N
CAN OCCUR BEFORE THE ONSET OF D M
IGT
OGTT--------SMALL FIBER D N
PAINFUL P N(UNKNOWN CAUSE)SHOULD
BE UNDERGO OGTT
TREATMENT INDUCED NEUROPATHY
LASSTS FOR WEEKS
DIABETIC NEROPATHIC CACHEXIA
ACUTE PAINFUL D N—DEPRESSIONINSOMNIA-WEIGHTLOSS -IMPOTENCE
M>F
ACRODYSTROPHIC NEUROPATHY
SENSORY LOSS-FOOT ULCER DISTAL JOINT
DESTRUCTION
CHRONIC FOOT ULCER---TRAUMA
ISCHEMIA
INFECTION
NEUROPATHIC ARTHROPATHY(CHARCOT
JOINT) -----FOOT ULCER-AUTONOMIC
IMPAIRMENT
D D SYPHLIS
DIABETIC PSEUDOTABES:LANCINATING
PAIN-LOSS 0F JOINT SENSATION
ABNORMALPUPIL
EMG&NCV ARE HELPFUL IN CONFIRMING
NCV -H REFLEX&AMPLITUDE OF SURAL
NERVE
ACTIVE DENERVATION POTENTIAL
DIABETIC AUTONOMIC NEUROPATHY
USUALLY CORRELATE WITH SEVERITY
OFSOMATIC NEUROPATHY
SUBCLINICAL-SEVER(HEART-GI-GU )
OH-RESTING TACHYCARDIA-H R
UNRESPONSIVE TO RESPIRATION------HALLMARK OFAUTONOMIC D N
OH—FAILURE OF SYMPATHIC&CARDIAC
COMPENSATORY IS IMPAIRED
D D---HYPOVOLEMIA-MEDICATION
VAGAL DENERVATION-----TACHYCARDIA IN
REST
SILENT MI
GI MOTILITY ABNORMALITY-FECAL
INCONTINENCE-DELAYED GASTRIC
EMPTYING(NAUSEA)-DIARRHEA-BACTRIAL
OVERGHOWTH-COLONIC
ATONY(CONSTIPATION)-BLADDER ATONY
IMPOTENCE
SUDOMOTOR ABNORMALITIES
DISTAL ANHIDROSIS
GUSTATORY SWEATING
PUPILLARY ABNORMALITIES
ASYMMETRIC PROXIMAL
NEUROPATHY(DIABETIC AMYOTROPHY)
BRUNS GARLAND SYNDROME
WEAKNESS OF PELVIFEMURAL MUSCLES
AGE>50YEARS
NIDDM—UNRELATED TO DURATION OF DM
SEVER PAININ LOWER BACK&HIP&TIGH
WEAKNESS—DTR-OPPOSITE LEG AFFECT
MINOR PARESTHESIAS-WEIGHT LOSS >50%
STEADY PROGRESSION-PAIN RECEDS
SPONTENOUSLY-RECOVERY UP TO 24 MON
66%OVERLAP WITH DISTAL DN
EMG:LOW AMPLITUDE-FIBS-
IMAGING:R/O OTHER CAUSES
SURAL NERVE BIOPSY(ISCHEMIA)
TRUNCAL NEUROPATHY
T4-T12 ROOTS INVOLVED
PAIN IN CHEST&ABDOMEN- BULGING OF
ABDOMINAL WALL-OLDER PATIENTS
NIDDM-ALLODYNIA-ABRUPT ONSET
D D:H Z-MASS LESIONS
RECOVERY:SEVERAL MONTHS
E M G:ACTIVE DENERVATION
FOCAL ANHIDROSIS
LIMB MONONEUROPATHY
MECANISMS:1-INFARCTION2-ENTRAPMENT
INFARCTION:ABRUOT ONSET-ACUTE
AXONAL DEGENERATION-SLOW RECOVERY
MEDIAN-ULNAR-PRONEAL(MOST COMMON)
ENTRAPMENT:INSIDIOUS ONSET-FOCAL
CONDUCTION BIOCKMULTIPLE MONONRUROPATHIES
ABRUPT ONSET-PROXIMAL NERVE-
NERVE INFARCTION DUE TO OCCLUSION
OF VASNERVORUM
D D:SYSTEMIC VASCULITIS
CRANIAL MONO NEUROPATHIES
THIRD NERVE PALSY IS MOST COMMDN
PUPILLARY SPARING
4-6-7TH ARE AFFECTED
ACUTE ISCHEMIC DAMAGE
RECOVERY:AFTER 3-5 MONTHS
INCREASED INCIDENCE OF ENTRAPMENT
NEUROPATHY
D M IS FOUND IN 8-12%PATIENTS WITH
CTS—25%DM PATIENTS HAVE
ELECTRODIAGNOSTIC CTS—
8%SYMPTOMATIC
RISK OF CTS---WOMEN 2/2 MEN 2/5 TIMES
REASON ? ISCHEMIA ORHYPOXIA
ENTRAPMENT----- POSSIBILITY OF DM
LABORATORY FINDINGS ;
CONFIRMATION OF DM:RANDOM BS>200mg
FBS>126mg/dl
2hpp>200mg/dl
IGT---- BS=140-200 FBS=110-126 mg/dl
EMG&NCV ABNORMALITIES
S>M
D>P
LEG>HAND
PATHOLOGY:SMALL VESSEL OCCLUSION—
IMMUNE MEDIATE—LOSS OF MYELINATED
FIBERS—AXONAL DEGENERATION
PAINLESS DISTAL D N----LARGE FIBER
PAINFUL DISTAL D N-----SMALL FIBER
PATHOGENESIS OF D N: NERVE BLOOD
FLOW- ENDONEURIAL VASCULAR
RESISTANCE– MYOINOSITOL-ACTIVATE
POLYOL PATHWAY------ALDOSE REDUCTASE)ACCUMULATION OF SORBITOL&FRUCTOSEAUTOOXIDATION
-ENDONEURIAL HYPOXIA:IMPAIRMENT OF
AXONAL TRANSPORT&REDUCE NERVE NA-K
ATP ASE ACTIVITY----- AXONALATROPHY
TREATMENT
OPTIMAL GLUCOSE CONTROL
INSULIN PUMP----AT 5 YEARS REDUCE 64%
PANCREAS TRANSPLANTATION PREVENTS
OF DN
MYOINOSITOL ? ALBERSTATIN ?
LIPOIC ACID----IMPROVED SENSORY
SYMPTOMS(AND ALSO C PEPTIDE)
VEGF----- NERVE BLOOD FLOW
IV METHYL PREDNISOLONE—IVIG
SYMPTOMATIC O H:6-10 INCHES HEAD
ELEVATED—DRINKING TWO CUPS OF
COFEE—EATING MORE FREQUENT SMALL
MEALS—DAILY FLUID INTAKE&SALT
INGESTION(10-20gr/d)-ELASTIC BODY
STOCKING-FLUDROCORTISONE(/1-/6mg/d)
NSAIDS(IBUPROFEN)PHENLPROPANOLAMINEMETOCLOPRAMIDE-TETRACYCLINE OR
ERYTHROMYCIN-CLONIDIN
G U COMPLICATIONS-----UROLOGIST
FREQUENT VOIDING-MANUAL ABDOMINAL
COMPRESSION-INTERMITTENT
CATHATERIZATION—SILDENAFIL-PROPER
SKIN CARE
Management of neuropathic pain
30-50% reduction of pain
ASA-acetaminophen-NSAIDs
TCA block of serotonin &NE reuptake
amitriptyline(10-25mg)-desiprmine
nortriptyline
SSRI are less effective
Venlafaxine has fewer side effect than TCA
150-225 mg/day
Duloxetine 60-120 mg/day moderate effect
Bupropion 300 mg/day 30%reduced pain
Anticonvulsants:
Carbamazepine 1000-1600mg/day
Oxcarbazepine 1200mg/d
Gbapentin300mg/d--------900-3600mg/d
Pregabalin150-600mg/d
Topiramate has minor effect
Lamotrigine200-400mg/d moderate relief
Mexiletine (oral analog of lidocaine) ?
Tramadol 200-400mg/d
Dextromethorphan high dose---partial relief
ataxia-sedation
Narcotic analgesics should be limited
Topical agents: capsaicin cream o.o25 or o.o75
patches containing 5% lidocain
G. B .S
Non seasonal illness
M>F 1.5/1
1.8/100000
Preceding event 2/3 of patients(1-4weeks before)
URI,GI infection,surgery,immunization
CMV-EBV-VZ
Hepatitis A&B
H.FLU Campylobacter jejuni 26%
SYMPTOMS& SINGNS
-Weakness+paresthesis
Ascends proximally over
Hours to several days
DTR
Progression
1-4 weeks
Cranial nerve palsy 45-75%
Facial paresis usually bilateral
BIH(rarely)
-Facial myokymia
Respiratory failure 12-30%
Sensory loss
Pain 85%
Pharingeal-cervical-brachial variant
Autonomic dysfunction 65%
LAB FINDINGS
CSF
EMG& NCV
LFT(transient)33%
Hyponatremia
Hematuria &proteinuria
MRI of LS
D.D*
Porphyria-Diphtheria-Intoxication(arsenicthallium)-Hypokalemia-HypophosphatemiaMyopathy-Tic paralysis-Botulism-Brain stem
stroke-Spinal cord compression-Transverse
mtelitis-Polyomyelitis
TREATMENT*
Respiratory support-Heparin-IVIG-Plasma
exchange-Symptomatic therapy- PT
Case Study
Case Study: Atropine Ophthalmic
Administration Unmasking Undiagnosed
Diabetic Gastroparesis
Roger Kenneth Eagan, MD and Pninit Varol,
MD
Presentation
R.R. is a 62-year-old white man with
glaucoma and long-standing type 2 diabetes
complicated by peripheral neuropathy and
retinopathy. He presented to the emergency
room with persistent nausea and vomiting.
The patient was admitted with presumed
symptomatic glaucoma. Three months earlier,
he had undergone pars plana vitrectomy
surgery for a vitreal hemorrhage secondary to
a diabetic tractional retinal detachment. The
patient had developed subsequent neovascular glaucoma
and had been instructed to use his ophthalmic medications to
control symptoms.
Several weeks before his emergency room visit, he began to
experience left eye pain. The patient was seen by his
ophthalmologist, who diagnosed increasing intraocular pressure
(IOP). The ophthalmologist intensified his regimen and
encouraged the patient to carefully follow the provided regimen.
Soon after, R.R. began to suffer from progressive nausea and
vomiting.
At the time of presentation, the patient had been unable to keep
solids or liquids down for several days. He was admitted and
treated with intravenous fluids and promethazine, then
discharged after 24 hours with arrangements for surgery the
following week. The following day, he returned with ongoing
intractable nausea and vomiting with opthalmalgia. He
underwent a successful shunt placement to relieve his IOP,
which relieved his opthalmalgia. However, he continued to have
severe nausea and vomiting. The ophthalmology service
requested a medicine consult for further evaluation of the
nausea and vomiting.
The internal medicine consultant found R.R. to be in significant
distress with intractable vomiting. His vital signs showed a
temperature of 98.6°F, heart rate 88 bpm, respiratory rate 14,
and blood pressure of 189/82 mmHg. Per ophthalmology, the
eye appeared well with ongoing normal IOP. Heart and lungs
were unremarkable. His abdominal exam was unremarkable.
Neurological exam demonstrated decreased sensation in the
feet in a stocking pattern with no other appreciable defects. A
work-up for common causes of intractable nausea and
vomiting using laboratory and radiological evaluation was
unremarkable.
The diagnosis of gastroparesis was entertained. His atropine
ophthalmic solution was discontinued. The patient's symptoms
improved such that he was again able to take food by mouth.
Ophthamology, however, felt that for the long-term benefit of
his eyes, it was imperative that the patient be restarted on the
atropine ophthalmic solution. Following reinstitution of the
ophthalmic atropine, his nausea and vomiting returned.
A gastric emptying study using Tc-99m sulfur colloid was
obtained. It showed gastric emptying delay of 43.9%
(normal range 8-28%). To optimize symptom
management and maintain the necessary ophthalmic
regimen, metoclopramide and erythromycin were begun
with good symptomatic relief.
Epilogue. Upon further questioning, R.R. and his wife
reported a gradual decrease in his meal sizes and increase in
meal frequency over the past year. He most likely had been selfmanaging his progressive diabetic gastroparesis. With the
addition of the anticholinergic medication, his underlying diabetic
gastroparesis became clinically apparent, leading to his admission
and subsequent work-up and diagnosis.
R.R. was eventually taken off the atropine ophthalmic drops, but
continued to have mild symptoms of diabetic gastroparesis.
Therefore, he was continued on metoclopramide with success.
Questions :
Can atropine ophthalmic solutions be absorbed in
clinically significant amounts?
Is systemic absorption of other ophthalmic drugs
known to be clinically significant?
What is a reasonable approach to use with
patients on ophthalmic agents?
Commentary :
Patients with diabetes are known to develop
autonomic regulatory problems. Because of this,
they can be especially susceptible to medications
that have effects on the autonomic nervous
system. Oral preparations of ß-blockers and
tricyclic antidepressants have been well
described. However, we rarely think of ophthalmic
agents in this light. It would make intuitive sense
that if systemic absorption of ophthalmic agents
can attain sufficient serological levels, there
would be an expected clinical effect.1,2
From our review of the basic science literature, we have
determined that the atropine ophthalmic solutions are readily
absorbed from the nasal and gastric mucosa.3,4 One study that
measured biologically active atropine (1-hyoscyamine) in sera
following ocular and intravenous administration noted
surprisingly similar concentrations.3 We performed a Medline
literature search and found only a few references to the clinical
systemic effects that can ensue from the ophthalmic use of
atropine.5 We were unable to find any cases of diabetic
gastroparesis unmasked by atropine ophthalmic solutions. We
also contacted the pharmaceutical makers of the atropine
preparation and were informed that no similar event had been
reported. It is our assertion that given the above bioavailability
information, undiagnosed clinical side effects are more prevalent
than the literature reflects.
One of the challenges of primary care physicians is
to monitor patients' medication lists. With our subspecialist colleagues adding medications appropriate
to the conditions they are managing, sometimes side
effects and interactions will occur. The ophthalmic
drops sometimes are overlooked in this process.
There can be significant systemic absorption of
these ophthalmic drops. The effects of ß-blocker
ophthalmic solutions on the cardiovascular and
respiratory systems have been widely discussed.
However, all of the following ophthalmic agents have
consistent data showing systemic effects:
prostaglandin analogs, adrenergic agonists, carbonic
anhydrase inhibitors, and cholinergic agonists.6
The following is our approach to patients on these
ophthalmic medications.
To minimize the systemic absorption of all ophthalmic agents, patients should
be directed to strictly instill the prescribed dosage only.
They should be further instructed to compress the lacrimal sac for 2-3 minutes
after installation of the eye drops.
Patients and clinicians need to be aware of the possible systemic side effects
and be diligent in monitoring for them. It is therefore recommended that, at the
follow-up visits, a brief, focused history and physical exam should be performed
targeted towards these side effects.
If side effects are noted, patient education should be reviewed.
If clinically significant symptoms remain, a dialogue among primary care
physician, sub-specialist, and patient should be undertaken weighing the risk
and benefits of ongoing administration.
Clinical Pearls :
All medications with autonomic modulating
properties should be given with caution to
patients with diabetes.
All ophthalmic agents should be monitored for
symptoms of systemic absorption.
Proper patient education can help minimize the
amount of ophthalmic drug absorbed
systemically.