tips and tricks

toxic neuropathies.

• Most toxic neuropathies occur together with exposure to the toxin.
  
• The duration and level of toxin exposure usually correspond to neuropathy severity.
  
• The most common pattern is a length-dependent axonal neuropathy.
  
• Withdrawal of the offending agent is the primary treatment goal.

Patterns of Neuropathy Associated with Toxic Exposure

The most common pattern of neuropathy is a length-dependent axonal neuropathy. Other less common patterns associated with toxic exposure include a sensory neuronopathy pattern and toxic channelopathy. Toxic exposure can cause a distinct pattern of a sensory neuronopathy and distal (length-dependent) axonal neuropathy based on the increased permeability of the blood–nerve barrier at the dorsal root ganglion and distal portions of the axon. As a result chemical and pharmaceutical agents have more direct effects on the neuronal cell body and their corresponding axons at these regions. Common agents include cis-platinum, pyridoxine, linezolid, metronidazole, podophyllotoxin, taxanes, and thalidomide. The gold salts, oxiplatinum, and several marine toxins can affect voltage-gated sodium and potassium channels (i.e. toxic channelopathies) and are characterized by paraesthesiae, cramps, stiffness, and fasciculations.

Other patterns of neuropathy are uncommon for toxic exposures. Isolated mononeuropathies should raise the suspicion of accidental injection of agents such as analgesics or antibiotics directly into the nerve. Usually such cases are easy to distinguish based on the clinical history. Multifocal neuropathies rarely result from toxins and underlying inflammatory or vasculitic causes should be sought. The toxic demyelinating neuropathies are also uncommon. Exceptions include arsenic or diphtheria with predominantly motor neuropathies associated with areflexia and cranial nerve abnormalities.

Evaluation of Toxic Neuropathies

The general approach to toxic neuropathies is similar to that for all neuropathies (see Chapter 20). The main area of emphasis is on potential exposure to toxic agents. In addition, a full medication history is necessary including past pharmaceutical agents, chemotherapeutic agents, antibiotics, and other illicit drugs. The timing and duration of use of these agents in relationship to the clinical presentation must be defined as specifically as possible.

Nerve conduction studies (NCSs) and electromyography (EMG) can be useful in further determining the pattern of neuropathy. In addition, NCSs can provide clues such as patterns consistent with hereditary neuropathies such as Charcot–Marie–Tooth disease (CMT) type 1A (highly susceptible to injury with chemotherapeutic agents) or acquired inflammatory neuropathies such as Guillain–Barré syndrome (due to the acuity may prompt a search for an underlying toxic exposure).

Standard blood work to investigate the potential for vasculitic/collagen vascular disease, inflammatory processes, diabetes, vitamin deficiencies, thyroid dysfunction, and monoclonal gammopathies are of use to rule out potential causes of neuropathy.

Nerve biopsy can be of use to rule out other important causes of neuropathy, most importantly vasculitic neuropathies, infective neuropathies such as leprosy, or amyloid neuropathy. Sural nerve biopsy may provide a pattern of nerve involvement (i.e. axonal rather than demyelinating) consistent with most toxic neuropathies, but would have an extremely low likelihood of providing a specific tissue diagnosis.

Basic Management Principles of the Toxic Neuropathies

The main principle in the treatment of the toxic neuropathies is obviously the immediate withdrawal of the offending agent. Specific treatments options are discussed further under the specific individual toxic agents. Prognosis depends on both the specific agent and the severity of the neuropathy and is discussed below.

Neuropathies Associated with Environmental, Occupational, and Industrial Toxins.

Ethylene oxide, methyl bromide, hexacarbons, and thallium can all cause neuropathy. These neuropathies are usually length dependent and predominantly axonal. The presentation is predominantly sensory to sensory motor dysfunction, depending on the severity of chemical exposure.

Lead Neuropathy

Industrial exposure accounts for the majority of lead neuropathy, which typically causes wrist and finger extensor weakness with later involvement of other muscle groups. Sensory involvement is uncommon but length-dependent sensory and motor dysfunction has been described with more long-term exposure. Acute exposure to high concentrations of lead is associated with motor predominant neuropathy in adults. In the acute form, elevated blood lead and erythrocyte protoporphyrin levels can be measured. The rapid withdrawal of the offending agent is associated with a more favorable prognosis. Chelation therapy is controversial.

Neuropathies Associated with Drug and Pharmaceutical Agents.

Numerous pharmaceutical agents can produce a peripheral neuropathy including amiodarone, bortezomib, colchicine, disulfiram, ethambutamol, metronidazole, phenytoin, and nucleoside analogues. The neuropathy in these cases is usually sensory or sensorimotor and length dependent. Dapsone is unique because it can cause an almost isolated motor axonal neuropathy. Chemo­therapeutic agents, including platinum-based compounds, taxanes, and vincristine, can all produce a sensorimotor neuropathy that is primarily axonal and length dependent.

Ethanol as a direct cause of neuropathy is debatable. Given the association of poor nutrition with increased alcohol intake in people with neuropathy, some authorities argue that the neuropathy is potentially related to thiamine deficiency. However, there is some evidence for a direct toxic effect of ethanol on the peripheral nerve. Irrespective, in a patient with a suspected alcohol-related neuropathy, a nutritional deficit must be ruled out.

Pyridoxine (vitamin B₆) can induce a sensory predominant neuropathy with prolonged oral intake (200–10 g/day). More significant intake, including intravenous administration, can produce a more rapid sensory neuronopathy. Symptoms can include diffuse sensory, limb ataxia, lost reflexes, and autonomic dysfunction. There is usually satisfactory neurological recovery with stopping pyridoxine in less severe cases.

Metabolic Neuropathies

General Principles

Metabolic neuropathies related to mineral or vitamin deficiencies are relatively limited in scope. The vast majority of these neuropathies are modest, with a length-dependent axonal pattern and are predominantly sensory. They are usually associated with malabsorption, intestinal dysfunction, or surgery/resection or malnutrition. Important clues to these types of neuropathy include the presence of ataxia in addition to the neuropathy and central nervous system involvement, which is usually more severe than the peripheral dysfunction. Features of a myelopathy in addition to the neuropathy should raise suspicion for these types of neuropathies.

Management and treatment principles are relatively straightforward. Diagnosis can be made on the basis of tests for specific mineral or vitamin deficiencies which are readily available and relatively inexpensive. Treatment is based on reversing any causative factors and replacement of the underlying nutritional deficiency.