Clinical manifestations

Presentation and course

The neuropathy associated with perhexiline in humans usually develops gradually after treatment periods of several months to years at the commonly used dosages of 200 mg to 400 mg daily (11; 05; 20; 28; 12). The anatomic pattern is that of a symmetrical sensorimotor polyneuropathy, beginning with acral pain and paresthesias and evolving to both proximal and distal weakness. There may be facial diplegia, perioral numbness, or autonomic dysfunction (05; 20). There is hypo- or areflexia and stocking hypesthesia. Perhexiline is occasionally associated with raised intracranial pressure and papilledema, with or without peripheral neuropathy (25; 06). This is perhaps related to elevated CSF protein content, although this is unclear. Improvement occurs within a few weeks of stopping the drug. A single patient is described with acute proximal weakness, rash, and an EMG with myopathic motor units and recruitment pattern; some doubt must nevertheless exist about this case, as the creatine kinase was normal, and no muscle biopsy was performed (26). Resolution occurred within 2 months of drug discontinuation. Systemic effects of perhexiline include weight loss, nausea, dizziness, and hepatotoxicity. Keratopathy is described, including the demonstration of cytoplasmic inclusions in conjunctiva and corneal epithelium (06).

Prognosis and complications

After drug withdrawal, recovery evolves gradually over months and may be incomplete in severe cases (11; 05; 20; 28; 12).

Biological basis

Etiology and pathogenesis

The clinical profile, electrophysiologic studies, nerve biopsy data, and experimental animal studies are consistent with a primary demyelinating polyneuropathy with associated axonal degeneration. The toxic mechanism is likely related to accumulation of lysosomal inclusions in Schwann cells and other tissues. Like amiodarone, perhexiline is a cationic amphiphilic drug that can penetrate lysosomes. It is postulated that such compounds form tight but not irreversible complexes with polar lipids, leading to impairment of degradation as well as to intralysosomal accumulation (13). The inclusions resemble those found in patients with various inherited storage diseases.

Perhexiline is absorbed within 6 to 12 hours of ingestion and has a half-life of 3 to 12 days. It is a lipophilic drug, can be found unchanged along with its metabolites in all tissues examined, and is eliminated in urine and feces after metabolic oxidation in the liver (cytochrome P450 2D6) to the more polar mono- and di-hydroxylated metabolites (29).

When fed perhexiline orally at 80 mg/kg per day for 4 to 10 weeks, dark Agouti rats, who are poor debrisoquine hydroxylators, develop cytoplasmic lipid inclusions similar to those in humans (15). These are most prominent in sensory and autonomic ganglia as well as in Schwann cells with primary demyelination in spinal roots and mixed demyelination and axonal degeneration in distal nerve segments. The number of inclusions are related to the duration of treatment as well as to the tissue and plasma concentration of perhexiline. There is a mild but statistically significant prolongation of motor latencies in sciatic nerve. Withdrawal of the drug 2 weeks before sacrificing the animal results in a decrease in inclusion bodies, indicating at least some degree of reversibility. Sprague Dawley rats, which are vigorous hydroxylators, show only mild accumulations of inclusion bodies, only after prolonged duration of treatment. In another study of adult Swiss NMRI-strain mice fed perhexiline for 10 to 18 weeks at 100 mg/kg per day to 200 mg/kg per day, inclusions were present in Schwann and perineurial cells of sciatic nerve as well as in gastrocnemius muscle biopsies (04). In both studies changes in animal weight, behavior, or nonquantitative measures of neurologic function were not noted. Perhexiline can induce polymorphous inclusions in the neurons, satellite, Schwann cells, and fibroblasts of cultured mice spinal ganglia (08).

Epidemiology

The incidence of symptomatic neuropathy may be low (17; 21), but subclinical electrophysiologic abnormalities are reported in up to two thirds of patients (21; 23).

Prevention

As with all drugs with potential neurotoxicity, perhexiline is best avoided or used judiciously in patients with preexisting neuropathy. Large interindividual variations in plasma half-lives (and thereby the risk of toxic drug accumulation) may be the result of genetically determined differences in rate of metabolism of the drug; poor debrisoquine hydroxylators (poor metabolizer phenotype) are at greater risk of developing neuropathy (24; 22; 23; 03; 02). The risk of toxicity can be reduced by maintaining plasma drug concentrations below 600 ng/ml (09). About 7% to 10% of United States and European Caucasians,1.9% of African Americans, and 1% of Asians harbor CYP2D6 mutations and are poor metabolizers (01). Attention to metabolizer phenotype and plasma drug levels can identify patients at risk and limit toxicity. Concern about the theoretical potential for synergistic toxicity of amiodarone and perhexiline has been allayed by a large series of patients, demonstrating safety when there has been previous tolerance of either agent and titration of plasma perhexiline concentrations guide therapy (07). In a study of 150 patients treated with perhexiline for a median of 50 months, therapeutic drug monitoring effectively limited the occurrence of toxic drug concentrations and virtually eliminated long-term hepato- and neurotoxicity (16).

Differential diagnosis

The temporal relationship to the drug and response to discontinuation will usually preclude the need to consider other possibilities, such as chronic inflammatory demyelinating polyneuropathy.

Diagnostic workup

The neuropathy should be established by clinical examination and characterized electrophysiologically. The temporal relationship to drug administration should generally be clear, and improvement with withdrawal of the drug should establish the diagnosis.

The CSF protein is typically mildly to moderately elevated up to several hundred mg/dl (11; 20; 25; 28; 12). There is mild to frequently-marked prolongation of distal motor latencies and slowing of motor and sensory conduction velocities to under 20 m/sec, consistent with primary demyelination (11; 20; 28; 12). Pathologic examination of human sural nerve biopsies, including teased fiber studies, shows primarily segmental demyelination along with loss of large myelinated fibers. In a study of 5 patients, Said found segmental demyelination of 16% to 90% of fibers and wallerian degeneration of 3% to 20% (20). Axons show few structural changes, and there is no inflammatory infiltrate (20; 04). Numerous polymorphic lysosomal inclusions are present mainly in Schwann cells but also in endothelial cells, fibroblasts, perineurial cells, phagocytes, and pericytes, as well as in hepatocytes, skin fibers and muscle fibers (20; 04; 08). Biochemical analysis of biopsy samples in 4 patients suggests that perhexiline-induced lipid storage consists mainly of gangliosides (18).

Management

Patients should be clinically monitored regularly for the development of neuropathic signs or symptoms, and the drug dose should be adjusted or usually discontinued.