1. Toxic
neuropathy
Tossif Ghodiwala
Peoples Friendship University of
Russia

2. Neither clinical nor laboratory
evaluation can distinguish
occupational neuropathies from
neuropathies due to other
causes.
Ref:
Occupational Peripheral Neuropathies
(MARCELLO LOTTI, MD; CHARLES E. BECKER, MD, and MICHAEL J. AMINOFF, MD, San
Francisco)

3. Peripheral neuropathies can be divided
into:
 Those which are bilaterally symmetrical—
polyneuropathies (for example, most neurotoxins)
 Those which are focal—mononeuropathies
 Multiple mononeuropathies (vasculitidies,
multifocal motor).

4. Other subdivisions are based on the
predominant site of dysfunction:
 Axons—axonopathies (organophosphates)
 Nerve cell bodies—neuronopathies (pyridoxine)
 Schwann cells and/or their myelin sheaths—
demyelinating neuropathies (acute arsenic
poisoning).

5. There are also different types of peripheral nerve
fibres: motor, sensory, and autonomic. Sensory
fibres are divided into at least three groups
anatomically, physiologically, and functionally:
 Aα (or Aαβ)—large diameter, myelinated, fast
conducting; mediating vibration, position, and
touch sensations
 Aδ—small diameter, myelinated, slow conducting;
mediating cold sensation
 C fibres—very small diameter, unmyelinated, very
slow conducting; mediating hot and pain

6. distal axonopathy is the most common
form

7. Clinical

8. The clinical effect of a polyneuropathy depends on
1) what modalities involved
2) what fibers are effected
3) whether the injury is axonal or demyelinating.
Adapted from http://www.neuroanatomy.wisc.edu/SClinic/Weakness/Weakness.htm

9. Loss of function
“- symptoms”
Disturbed function
“+ symptoms”
Motor nerves Wasting
Hypotonia
Weakness
Hyporeflexia
Orthopedic deformity
Fasiculations
Cramps
The clinical response to motor nerve injury

10. www.neuro.wustl.edu/neuromuscular/pics/people/patients/Hands/handatrophymnd3.jpg

11. Loss of function
“- symptoms”
Disordered function
“+ symptoms”
Sensory
“Large Fiber”
↓ Vibration
↓ Proprioception
Hyporeflexia
Sensory ataxia
Paresthesias
Sensory
“Small Fiber”
↓ Pain
↓ Temperature
Dysesthesias
Allodynia
The clinical response to sensory nerve injury

12. Loss of function
“- symptoms”
Disturbed function
“+ symptoms”
Autonomic nerves ↓ Sweating
Hypotension
Urinary retention
Impotence
Vascular color changes
↑ Sweating
Hypertension
The clinical response to autonomic nerve injury

13. Axonal Demyelinating Mixed
Sensory Sensory & Motor Motor
Lead
Nitrous oxide
Acrylamide
Alcohol
(Ethanol)
Allyl chloride
Arsenic
Cadmium
Carbon
disulfide
Cobalt
Colchicine
Cyanide
Ethylene oxide
Lithium
Methyl
bromide
Organophosph
ates
Botulism
Lead
Mercury
Buckthorn
Hexachlorophe
ne
Muzolimine
Perhexiline
Porcine brain
Procainamide
Tellurium
Diethylene
glycol
Ethylene glycol
Gold
Hexacarbons
n-Hexane
Na+ Cyanate

15. Allyl chloride
Toxicity
• Uses: Manufacture of epoxy resin & glycerin
• Atmospheric exposure
• Outbreaks in Chinese
• Neuropathy
• Distal
• Sensory > Motor
• Axonopathy; Distal
• Recovery: Months; Following toxin withdrawal
• Pathology
• Distal axonopathy
• Multifocal neurofilament accumulations
• CNS: Dorsolateral columns

16. Arsenic (inorganic)Toxicity
 Sources: Suicidal, Homicidal, Occupational,
Environmental
 Mining
 Inorganic arsenic: Exposure to by-products of copper & lead
smelting
 Ingestion of trivalent arsenic
 Suicide
 Homicide
 Food or water contamination: Endemic regions
o Groundwater contamination
o Locations: West Bengal, India; Bangladesh; Inner
Mongolia
o West Bengal, India
• 6 million people exposed to arsenic through drinking water
• 300,000 people manifest signs of chronic arsenicosis
 Contaminated opium: Punjab

17.  Clinical syndromes: Dose related
 General: Garlic-like smell to breath & tissue fluids
 Massive overdose: Subacute neuropathy
 Early
 GI: Vomiting & Diarrhea; Probably 2° GI irritation
 Autonomic: Tachycardia & Hypotension; 2° GI fluid loss
 Neuropathy
 Onset
 Delayed: After 10 to 20 days
 Distal paresthesias & numbness
 Evolution
 Over 2 to 5 weeks
 Sensory > Motor
 Large fiber sensory modalities
 Systemic signs: Few
 Pathology: Distal axonal loss ± Demyelination
 Treatment: Chelation with BAL or penicillamine for months
 Recovery: Slow over years

18. Hexacarbons
Toxic compounds
 n-Hexane
 n-butyl ketone
 2,5-hexanedione
 Metabolism
 n-Hexane & n-butyl ketone metabolized to active agent:
2,5-hexanedione
 2,5-HD half-life: 13--14 hours; Accumulation may occur
during workweek
 Detection: Acid-hydrolyzed urinary levels of 2,5-HD
 Sampled at the end of a shift
 Correlate with workplace concentrations of n-hexane

19.  Uses
 n-Hexane: Glues & Lacquers: Solvents
 Exposure: Glue sniffing; Gasoline sniffing; Occupational
 n-butyl ketone: Solvent
 Exposure routes
 Common: Airborne
 Occasional: Dermal; Latex gloves not effective
protection
 Exposure limit: 50 ppm
 Epidemiology
 Young males: Glue sniffing; Gasoline sniffing
 Occupational: Auto mechanics; Printing plants; Sandal
shops; Furniture factories
 Geography: Asia; Europe; US
 Neurotoxic effects of n-hexane may be intensified
 Use with other chemicals: Acetone, MEK, Isopropanol

20.  Chronic low dose exposure: Neuropathy
syndromeExposure: Gasoline sniffing , Shoemakers
 Onset
 Subacute or Slowly progressive: 2 months
 Sensory loss: Distal
 Paresthesias
 Weakness
 Distal > Proximal
 Legs > Arms
 Distribution
 Symmetric: Most common
 Mononeuritis multiplex: Rare; ? Due to nerve compressions
 Sensory
 Loss
 Distal; May progress to proximal involvement
 Hands & Feet
 Large & Small fiber modalities
 Paresthesias
 Distal
 Hands & Feet

21.  Tendon reflexes: Absent or Preserved except at ankles
 Recovery: With delay after removal of toxin
 Progression ("coasting") for 1 to 4 months
 Improvement: Months to years
 Residual deficits in more severe cases
 Distal sensory loss & weakness
 ± Spasticity
 CNS
 Encephalopathy: Hallucinations
 Myelopathy: Occasional; Delayed onset; Spasticity
 Systemic disorders
 Weight loss
 Malaise & Anorexia
 Abdominal pain
 Electrodiagnostic
 SNAPs: Subclinical exposure to 2,5-hexanedione can reduce
amplitudes

22.  LaboratoryCSF: Normal
 Electrophysiology: Axonal loss + Features of
demyelination
 Axonal loss: Small CMAPs
 Conduction block
 Partial; Non-focal (Graded); Distal (Forearm & Leg)
 Especially rapid onset cases exposed to high doses
 Glue sniffing more than chronic industrial exposure
 In progressive phase of disease
 Late: Disproportionate distal slowing of NCV
 CNS: Abnormal visual & auditory evoked potentials

23.  Pathology
 Distal axonopathy
 Giant neurofilamentous swellings
 In PNS & CNS
 At proximal sides of nodes of Ranvier
 Distal, non-terminal regions of axons ® Progress proximally
 Consist of 10 nm neurofilaments
 May produce 2° demyelination: Thin myelin sheaths
 Axoplasmic transport may be impaired
 Nerve biopsies may be normal with mild disease
 Treatment: Removal from n-hexane exposure

24. Lead
 Epidemiology of lead toxicity
 Common in children: Especially black non-hispanic
children (22%)
 Most common in homes built from 1920 to 1950
 Identical twins often have concordant lead levels
 Lead neuropathy: Especially from industrial
exposure
 Exposure: Most common with ingestion & inhalation
 Sources
 Ingestion: Paint; Moonshine whiskey; Rum processed in
lead pipes; Asian folk medicines9
 Occupational: Smelting; Battery manufacture; Demolition;
Auto radiator; Silver refining

25.  Neuropathy: Motor
 Exposure: Subacute to high environmental lead
concentrations
 Patterns of weakness: Variable
 Childhood: Lower extremity
 Adults
 Arms (Wrist & Finger extensors) > Legs
 Distal > Proximal
 Asymmetric
 Recovery: Good with elimination of exposure, unless severe
weakness
 Variants
 Severe exposure: May produce quadriplegia
 Chronic low level exposure: No weakness
 Older literature: Focal weakness
o Wrist & finger extensors
o Proximal shoulder
o Hand intrinsic muscles
o Peroneal muscles
o Laryngeal paralysis

26.  Associated disorders
 Pain: Abdominal; Headache; Joint
 General: Fatigue; Irritability
 Anemia
 Sickle cell disease
 Electrophysiology
 Motor
 Axon loss
 Mild cases: Prolonged distal latencies or Normal
 Sensory
 Vibratory thresholds: Increased
 Mild slowing of NCV
 Pathology
 Humans: Axonal degeneration
 Experimental animals
 Segmental demyelination
 Endoneurial edema
 Recovery: Slow improvement

27.  Neuropathy: Sensory
 Chronic low level lead exposure: Often decades
 Distal; Legs > Arms; Symmetric
 Subclinical changes common
 CNS
 Encephalopathy in children: Lethargy; Ataxia; Dysarthria
 Severe: Cerebral edema; Seizures
 Chronic
 Intellect impaired in dose dependent fashion
 More severe: Exposure at 2 years; Long duration of exposure
 Systemic features
 GI: Constipation; Abdominal pain
 Renal failure
 Hypertension
 Gums: Blue discoloration

28. Basophilic
stippling
•Lab
•Hematologic: Mild anemia
•Hypochromic & Microcytic
•Basophilic stippling of erythrocytes
•Always present with neuropathy
•Uric acid: Low
•CSF: Usually normal
•Urine
•Coproporphyrin: High
•Lead: High (> 0.2 mg/L); Related to intake
•Blood lead levels
•Usual test for lead exposure
•Symptoms usually with levels > 80 μg/dL
•Not accurate indicator of degree of symptomatology or body burden
•Radiology
•Bones: Lead lines
•GI: Paint chips in GI tract with acute ingestion

29.  Treatment
 Elimination of exposure
 Chelation: Children > 25 μg/dL; Adults > 70 μg/dL
 Penicillamine: Mild intoxication < 70 μg/dL
 Succimer (DMSA)
 Ca-Na2 EDTA: Lead level > 70 μg/dL
 BAL: Added with severe toxicity
 Dimerval (DMPS)

30. Work-out

31. Diagnosis
 Take a thorough medical history, including the
patient’s occupational and environmental history,
to consider all sources of exposure to all possible
agents.
 List details of all jobs and specific tasks within
these jobs, as well as when various symptoms
and medical problems began for the patient.

32. Quantitative sensory testing in the
diagnosis of neuropathy includes the
following:
 Vibration threshold
 Thermal threshold
 Portable motor and sensory latency
 Current perception threshold (CPT)

33. Other studies that help to prove the
presence of neuropathy include the
following:
 Intraepidermal nerve fiber density (IENF)
 Sympathetic skin reflex
 Electromyography (EMG)
 Nerve conduction

34. Laboratory studies in patients with
neuropathy can include the following:
 Glucose tolerance
 Serum, urine, or blood
 Vitamin B-12
 Monoclonal gammopathy of unknown significance
 Axonal neuropathy
 Cryoglobins and hepatitis C evaluation
 Immunofixation (for paraneoplastic neuropathy)
 Cerebrospinal fluid (CSF) protein level: Usually
normal in toxic neuropathy

35. Management

36. Medical Care
 Advise removal from occupational or
environmental exposure.
 Advise discontinuation of medication or
recreational drug habit. Also provide information
regarding how alcohols affect those with
exposures.
 Preventive care and supportive care should
include consideration of life stressors, diet, and
overall behavior modifications.

37. Treatment options also include the following:
 Nonpharmacologic options include cool soaks,
heat, massage, elevation or lowering of the limbs,
shoe tightness, and/or exercise.
 Pharmacological options include tricyclic
antidepressants, anticonvulsants, opiates, or
topical capsaicin cream. Other options include
intravenous gamma globulin, aldose reductase
inhibitors, nerve growth factor, anti–tumor
necrosis factor-α; these are mainly research
ideas.
 Three that may be helpful presently include lipoic
acid, evening primrose, and vitamin E.

38.  Alpha lipoic acid is well reviewed by Halat and
Dennehy. Thiolic acid is a free radical scavenger
and chelator. It is approved for use in Germany
for neuropathy. The best studies suggest
parenteral use followed by oral use relieves
symptoms and improves nerve blood flow. Oral
preparations are available in United States. Two
studies suggest increased nerve conduction
(600/1200 mg for 2 y, oral) and reduced
symptoms (1800 mg/d for 3 wk, oral). The
mechanism of action includes chelation and, thus,
a concern for mineral shortage exists. Monitoring
iron levels is suggested, and persons with

39.  Evening primrose is also well summarized by
Halat and Dennehy.[58] It includes omega 6
essential fatty acids: gamma linoleic acid (GLA)
and linoleic acid. It is an essential component of
myelin and the neuronal cell membrane. Dosages
ranging from 360-480 mg/d for 6 months to 1 year
improved nerve function measurements. It has
mild side effects including inhibition of platelet
aggregation. Concern also exists for those with
seizure disorders.

40.  Vitamin E is discussed in the article Argyriou et
al.[59] Vitamin E has been administered to
patients on chemotherapy for prevention of
neuropathy at doses of 600 mg/d during
treatment and then for 3 months after treatment.
A reduced peripheral neuropathy score has been
noted. A neuroprotective effect has been
described

41. Consultations
 Occupational therapist
 Environmental medicine specialist

42. Diet
 Although diet does not play a specific role in
reparation of the PNS, a balanced diet is
important for various reasons related to general
health. Since various B vitamins have been
implicated in the development of neuropathies,
some physicians suggest supplementation.

43. Further Outpatient Care
 Consistent follow-up care with a neurologist is
necessary to monitor the progress of neurological
findings.
 Follow-up with an occupational medicine specialist
may be important to assist with return to work and
reduction of exposure. This clinician may be able to
work with the company supervisors or management to
improve the work environment. This may occur if the
company chooses to substitute the neuropathy-
causing agent with a less-toxic agent in the
workplace, to change the schedules of workers so
that their exposure is less during a period of time, or
to promote safer personal protective equipment.
Communication between health care provider and
management is essential for this individual's health as
well as his or her status for disability or ability return

44. Prognosis
 Each patient's prognosis depends on the severity
of the neuropathy when exposure is ceased or
reduced to levels that will not affect health
negatively.

45. Patient Education
 Inform patients about aspects of dose, diet, and nutrition
that may increase risk of toxicity when taking a medication.
Since many solvents are metabolized in the liver,
concomitant use of medications with similar metabolism
may lead to increased toxicity.
 Workers, by law, need to be informed of chemicals in the
workplace and their potential health hazards. Material
safety data sheets (MSDS), per order of Occupational
Safety and Health Administration (OSHA), are available to
all workers in the workplace.
 The Emergency Planning and Community Right to Know
Act (EPCRA) requires that facilities using, storing, or
manufacturing hazardous chemicals make public inventory
and report every release to public officials and health
personnel. These facilities must cooperate with health
personnel who are treating victims of exposure.