charcot-marie-tooth prevalence:1/2500 type1:begins in first or second decade manifestations: a...
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Charcot-Marie-Tooth Prevalence:1/2500type1: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 NEUROPATHY5% PER YEARS
RETINOPATHY-NEPHROPATHY-NEURDPATHY
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 CONCENTRATIONRISK FACTORS WITH ON INCREASED FOOT SENSATION :POOR GLYCEMIC CONTROL-HEIGHT-AGE-ALCOHOLEMG&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—DEPRESSION-INSOMNIA-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&LITUDE 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 BIOCK-
MULTIPLE 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&FRUCTOSE-AUTOOXIDATION
-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)-PHENLPROPANOLAMINE-METOCLOPRAMIDE-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(arsenic-thallium)-Hypokalemia-Hypophosphatemia-Myopathy-Tic paralysis-Botulism-Brain stem stroke-Spinal cord compression-Transverse mtelitis-Polyomyelitis
TREATMENT*Respiratory support-Heparin-IVIG-Plasma exchange-Symptomatic therapy- PT
Case StudyCase 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 self-managing 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 sub-specialist 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.
