Friday, 11 March 2016

Watch Out For Medications That Actually Cause Neuropathy Themselves!

Today's post from (see link below) is highly technical and mentions many drugs you may never have heard of but is nevertheless a very useful article. If only more experts in the field exposed dangerous drugs in this way, many people might be spared the agonies of neuropathy. However, that is easier said than done and when you think of the complexity of the drugs we use for all other conditions, it's maybe little wonder that, despite their effectiveness in treating the main target problem, one of their side effects can be nerve damage. That said, it's the job of pharmaceutical companies and doctors to protect us (or at least warn us) from hidden side effects but sometimes, the achievement of success in treating one problem can be enough to forgive the emergence of another. Take chemotherapy as one glaring example: without it the cancer may not be tackled but with it comes a significant risk of neuropathy - sometimes it's a question of which is the greater evil/benefit. In war they call it 'collateral damage'. What this detailed article does tell us is that it's always important to check and know the chemical name of the drugs we are taking, because the brand names often hide a multitude of sins, If you use various trustworthy drug interaction check sites, you will need to know the drug's proper name in order to be able to check all its potential interactions and side effects. Unfortunately, most people with neuropathy also have other medical issues and are being treated for those as well, so it's vital to be able to trust any drug combinations and at least be forewarned of any possible problems.

Drug-induced neuropathies
By Louis H Weimer MD Etiology Article section 4 of 11. 

No broad etiology or pathogenic mechanism has been suggested, but isolated cases may be part of an acute hypersensitivity reaction (Glyn and Crofts 1966). Most of the potentially pathogenic mechanisms in this section are speculative.

Specific agents.

Allopurinol. Allopurinol has been used for the treatment of gout since its approval in 1966. Allopurinol inhibits the enzyme xanthine oxidase, which blocks the metabolism of hypoxanthine and xanthine (oxypurines) to uric acid, interfering with the catabolism of purines. A number of cases of neuropathy have been associated with this agent in reports with various strengths of association (Glyn and Crofts 1966; Worth and Hussein 1985; Azulay et al 1993). The initial description included a hypersensitivity reaction with later drug rechallenge with a subsequent repeat allergic reaction, which included symptoms and signs of peripheral neuropathy. The patient also received colchicine after symptom onset with unclear timing related to neuropathy onset. Symptoms improved but persisted after cessation (Glyn and Crofts 1966). Fewer than 10 cases have been noted in the literature with at least 2 cases having complicating issues (uremia). The most recent report included some electrophysiologically and pathologically demyelinating features (Azulay et al 1993). These features were not previously noted, and regression occurred after drug cessation. Most cases occur after several or many years of therapy. No predisposition or ancillary factors are currently known. No experimental evidence supports the association, making this a possible, but not a definite, rare idiosyncratic association. In fact, the agent has been used to preserve nerve and vascular function in streptozotocin-induced diabetic neuropathy in rats (Inkster et al 2007). Inhibition of xanthine oxidase produced reactive oxygen species is the suspected beneficial effect. Blood flow declines caused by the experimental diabetes were also partially corrected.

Almitrine. Almitrine bismesylate is not FDA approved for use in the United States, but it is available in many other countries for treatment of chronic obstructive pulmonary disease and some vascular disorders including stroke prophylaxis. Almitrine acts as a peripheral chemoreceptor agonist. The component is noteworthy because it appears to commonly induce a predominantly sensory neuropathy. In 1 small placebo controlled study of 7 controls and 5 treated chronic obstructive pulmonary disease patients, 3 of 5 treated patients and none of the controls developed significant neuropathy (Allen and Prowse 1989). Bouche and colleagues reported 46 cases of almitrine-associated neuropathy in one series (Bouche et al 1989). The range of onset described is 9 to 25 months after medication onset. Sensory symptoms restricted to distal legs involving all modalities are typical. Electrophysiology and nerve biopsy findings were consistent with sensory axonopathy (Gherardi and Baudrimont 1987; Petit et al 1987). Improvement is described in most cases and is usually complete after a year (Bouche et al 1989). Numerous other reports have been made that support the high incidence of neurotoxicity with this agent (Louarn 1985; Blondel et al 1986; Petit et al 1987; Allen 1988; Wouters et al 1988; Allen and Prowse 1989; Gherardi et al 1989). Small placebo control studies have reported variable, but significant, percentages of patients stopping trials because of neuropathic symptoms. Gherardi and colleagues have reported nerve biopsy and ultrastructural studies of 8 cases. The primary finding is axonal loss of large myelinated fibers with signs of regeneration in 1 delayed biopsy. In addition, signs including segmental demyelination on teased fiber preparations suggested a demyelinating component in a variable percentage of fibers. No animal studies are available for consideration. No predisposing conditions are known. Moreover, the severity of hypoxemia from the pulmonary disease does not appear to correlate with the appearance of neuropathy or subsequent improvement after cessation. One series did describe a shorter latency to neuropathy onset in chronic obstructive pulmonary disease versus vascular patients, but most were receiving higher doses. However, some additional neuropathological signs seen in isolated cases (microangiopathy) could be secondary to chronic hypoxemia. Weight loss is commonly associated with the appearance of neuropathy. Some studies using a lower dosage (< 100 mg/day) have shown no significant neuropathy, including electrophysiologic changes (Weitzenblum et al 1992). Recent series have reported no dropout due to neuropathy of patients who used similar dosages, but these series are without specific methods to detect sensory loss.

Amitriptyline. Amitriptyline is a useful drug in the treatment of painful conditions including peripheral neuropathy, especially conditions with marked small fiber mediated pain involvement. However, several reports have associated this agent and, even more rarely, other tricyclic antidepressants including imipramine with inducing peripheral neuropathy (LeWitt and Forno 1985; Leys et al 1987). Many of the cases described are in the setting of overdose with other complications including rhabdomyolysis and cholinergic effects on the CNS and periphery; however, a small number have described suspected neuropathy on conventional amitriptyline dosages with improvement after cessation (Isaacs and Carlish 1963; Nimmo Smith and Grieve 1963; Zampollo et al 1988). There is limited experimental evidence of ultrastructural lesions in cultured neurons and astrocytes, but this relation to human toxicity is speculative at best and has not altered use in patients with neuropathy.

Chloroquine. Chloroquine is an agent used to treat malaria prophylaxis and some autoimmune conditions. The primary neuromuscular complication is a vacuolar myopathy, which can be fulminant (Siddiqui 2007); however, rare cases of neuropathy with demyelinating features and axonal loss have been described (Wasay et al 1998; Stein et al 2000). Onset is typically 1 to 2 years after starting medication and involves both sensory and motor fibers. Severity is not typically marked. Schwann cells have shown dense and laminar cytoplasmic inclusions similar to those seen with amiodarone and perhexiline, notable other causes of demyelinating toxic neuropathy. Sural biopsies have shown axonal loss and segmental demyelination and remyelination (Tegner et al 1988). Electrodiagnostic studies have also suggested a neurogenic component superimposed on the predominant myopathy. Some have noted the pattern could mimic a polyradiculopathy. This effect has been reproduced in rats.

Cyclosporin. Cyclosporin A has been used as an immunosuppressive agent in numerous conditions including organ transplantation and even some cases of immune mediated neuropathy. Limited information has associated cyclosporin A with otherwise unexplained peripheral neuropathy. The evidence rates this agent at best as a possible, but not probable, causative agent at present (Blin et al 1989; Chan et al 1996).

Dichloroacetate is used experimentally to treat chronic lactic acidemia from mitochondrial diseases. Peripheral neuropathy is common with chronic dichloroacetate treatment. Clinical and electrophysiologic signs of sensorimotor neuropathy are found (Spruijt et al 2001; Anselm and Darras 2006; Kaufmann et al 2006). The neuropathy is significant but can be reversible over months if the drug is stopped. Neuropathy also develops in younger children with lactic acidosis but was said to be tolerated by most in one trial of 36 impaired children (Stacpoole et al 2008). The neurotoxic mechanism is not fully known, but the agent causes reversible demyelination in cultured rat Schwann cells and dorsal root ganglia neurons exposed to dichloroacetate for up to 12 days (Felitsyn et al 2007). The heme precursor delta-aminolevulinate is implicated in neurologic complications associated with porphyria and tyrosinemia type I. The compound is elevated in the urine of animals and humans on dichloroacetate and appears to damage Schwann cells in part by reducing the levels of myelin-associated lipids and proteins, including myelin protein zero and peripheral myelin protein 22 (Felitsyn et al 2008). It is currently unclear but suspected that patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) may be at increased risk of developing the toxic neuropathy. The drug is also under investigation in the treatment of glioblastoma multiforme. Dichloroacetate may help minimize treatment resistance mediated by changes in mitochondria that reduce cancer cell apoptosis in part by a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. However, studies in humans have been limited by dose-dependent peripheral neuropathy (Michelakis et al 2010).

Glutethimide. Glutethimide is a sedative-hypnotic agent originally used as an ethanol substitute, but it proved to be highly addictive in its own right. The compound was reclassified as schedule II and withdrawn from general availability in 1991. Chemically, the compound is structurally similar to thalidomide, an agent that more commonly induces sensory neuropathy. Rarely, neuropathy has been associated with chronic glutethimide use at high doses (Nover 1967; Haas and Marasigan 1968). Cerebellar ataxia is also described and may be marked and persistent. Manifestations are predominantly but not exclusively sensory and are supported by limited electrodiagnostic data. Improvement or resolution over ensuing months is described. No experimental evidence or nerve biopsy data are available for correlation.

Ixabepilone. The epothilones are a new class of chemotherapeutic agent with currently low tumor resistance. The class includes the natural agents, epothilone B (patupilone) and epothilone D, which are not yet FDA approved as well as the semisynthetic analog, ixabepilone (Bhushan and Walko 2008; Swain and Arezzo 2008); ixabepilone was FDA approved in October 2007. Breast cancer is the primary indication, but phase II studies are completed or are ongoing for a variety of cancer types. The group binds to tubulin similarly to certain other chemotherapeutic agents, such as vinca alkaloids and taxanes, but at differing binding sites. Similar to taxanes, the drugs promote dysfunctional stabilization of microtubules but with a differing mechanism, in contrast to microtubular destabilizing agents such as vincristine, colchicine, and podophyllotoxin (Cortes and Baselga 2007). Peripheral neuropathy from ixabepilone is a major dose-limiting side effect. Mild-to-moderate (grade 1 to 2), predominately sensory neuropathy that improves or resolves is most common, but more severe grades (grade 3) occur rarely in monotherapy and at rates of 10% to 15% with combination therapy or in patients previously exposed to taxanes or capecitabine; grade 4 neuropathy appears to be very rare (Denduluri et al 2007; Perez et al 2007; Roche et al 2007; Thomas et al 2007a). Dose reduction may be adequate in many, but treatment discontinuation occurs as well; more dispersed treatment protocols may have lesser toxicity (Thomas et al 2007b). Twenty-one percent of patients treated with ixabepilone plus capecitabine discontinued treatment because of sensory neuropathy in one large phase III trial (Thomas et al 2007b). Severity increases with cumulative dosing, especially after an average of 4 treatment cycles. The overall neuropathy incidence varies depending on dose and coincident treatments but is as high as 67%. The reported reversibility of sensory neuropathy is surprising considering the experience with other microtubule targeting agents such as vincristine and taxanes. One patient is reported who developed significant weakness associated with neuropathy after 1 treatment cycle (Bosch-Barrera et al 2009). Review of all phase 2 and phase 3 clinical trials found a 1% incidence of severe neuropathy in patients previously untreated and up to 24% of breast cancer patients treated with other agents (Vahdat et al 2012). Carefully monitoring for neuropathy and timely dose adjustment or treatment discontinuation is advocated depending on the neuropathy severity (Swain and Arezzo 2008). Neuropathy is increasingly recognized as a dose-limiting side effect and 20% dose reduction is one proposed strategy (Valero 2013). This entity is also discussed in the section on chemotherapy-induced neuropathy.

Leflunomide. The immunosuppressive prodrug leflunomide was FDA approved in late 1998 as a disease-modifying rheumatoid arthritis treatment. It was subsequently recognized that an axonal, sometimes painful, sensorimotor polyneuropathy is associated with leflunomide (Carulli and Davies 2002; Bonnel and Graham 2004; Metzler et al 2005). Eighty cases reported to the FDA were uncovered and described (Bonnel and Graham 2004). After this report, additional series have been reported identifying numerous additional probable cases (Bharadwaj and Haroon 2004; Martin et al 2005; Kho and Kermode 2007). Bharadwaj and Haroon describe 150 prospectively tracked rheumatoid arthritis patients in India. Fifty received leflunomide either as monotherapy or in combination with other drugs. Five developed new neuropathy (10%) in contrast to 2 of 100 receiving other treatments (2%). Nerve biopsy in 3 demonstrated epineural perivascular inflammation around small and medium-sized arterioles patchily affecting large and small myelinated nerve fibers suggesting a predominant axonopathy with features of vasculitis. All showed clinical improvement and were said to become asymptomatic within 3 months, but residual nerve conduction abnormalities remained (Bharadwaj and Haroon 2004). Kopp and colleagues describe a case and suggest a potential interaction between 5-FU and leflunomide and include the possible mechanism (Kopp et al 2005). Onset is usually after 3 to 6 months of drug use, although symptoms may appear sooner. Another study compared 16 rheumatoid arthritis patients treated with leflunomide with 16 others receiving alternative disease-modifying therapies. Neuropathy symptoms scores increased in 54% of the leflunomide group compared with 8% of the others; however, electrophysiology did not correlate with clinical symptoms (Richards et al 2007). Stopping therapy within 30 days of symptom onset gives a better chance of improvement, though recovery is typically slow. Sural nerve biopsies have shown nonspecific axonal loss in most, but signs of perivascular inflammation have been described. Primary rheumatoid arthritis is an independent neuropathy risk factor often associated with vasculitis, but leflunomide reports have not generally described this type of pattern. Neuropathy incidence is higher than with rheumatoid arthritis alone or with other rheumatoid arthritis medications. One retrospective analysis found increased associated neuropathy risk with increasing age, diabetes, and the use of other potentially neurotoxic medication (Martin et al 2007). The mechanism of neurotoxicity is not known; neuropathy cases were not detected in clinical trials. The drug remains an effective treatment and efficacy appears to be similar to methotrexate and better than sulfasalazine. However, withdrawal rates are higher than methotrexate because of toxicity; peripheral neuropathy is one of several forms of toxicity (Alcorn et al 2009). Comparison of 94 rheumatoid arthritis patients treated with either leflunomide or other disease modifying agents found significant differences in quantitative cold but not vibration perception measures; leflunomide-treated patients were roughly twice as likely to have increased cold perception measures (Kim et al 2012).

A similar agent, teriflunomide, is now approved in the United States to treat multiple sclerosis. Paresthesia and peripheral neuropathy are associated with this agent as well but the neuropathy risk and incidence are not yet known. Clinical trial data suggest an incidence of 1% to 2%, but no aftermarket reports of significant neuropathy cases are known.

Lipid-lowering agents. The statin-class of cholesterol medications acts by inhibiting the rate-limiting step in cholesterol synthesis, hydroxymethylglutaryl coenzyme A (HMG CoA). The predominant neuromuscular complication with these agents is a toxic myopathy referred to as cholesterol-lowering agent myopathy, which is well appreciated by physicians and patients. An increasingly recognized acute necrotizing myositis with rhabdomyolysis associated with antibodies against the HMG CoA enzyme can develop. However, a number of cases of peripheral neuropathy temporally associated with conventional doses of simvastatin and other agents in the class have been reported (Jacobs 1994; Ahmad 1995; Phan et al 1995; Ziajka and Wehmeier 1998; Jeppesen et al 1999; Lo et al 2003). Partial or complete recovery after drug cessation is described. One report described sural biopsy data demonstrating small and large fiber axonal loss (Phan et al 1995). Several cases have serial electrophysiological studies showing sensorimotor axonal neuropathy with variable levels of subsequent improvement. No experimental model to support the effect is known. Symptom onset has been described within days to as long as several years after onset. One case described neuropathy onset after several years of treatment with lovastatin; when treatment stopped, the condition improved (Ziajka and Wehmeier 1998). Rechallenge with pravastatin, simvastatin, and later atorvastatin each caused a subacute recurrence of burning dysesthesias that improved with cessation. Similar rapid worsening with rechallenge has been noted in other reports. One speculative mechanism proposed is that inhibition of mitochondrial hydroxymethylglutaryl coenzyme A reductase causes a subsequent decrease of ubiquinone synthesis, which potentially may disturb neuronal energy utilization (Walravens et al 1989).

Thus, only the temporal association with the neuropathy development and subsequent improvement was available to support a causative link until a case control study reported by Gaist and colleagues (Gaist et al 2002). Gaist and colleagues suspected a possible link between these agents and cases of idiopathic neuropathy, despite an earlier negative United Kingdom study (Gaist et al 2001). They then conducted a much larger population-based study in 1 Danish county (465,000 inhabitants) and cross referenced a prescription registry to a national patient diagnosis registry from 1994 to 1998, when statin use in Denmark increased from 11,547 to 50,318 nationwide. Gaist and colleagues identified 1084 registered patients with a diagnosis of polyneuropathy. They excluded 492 with onset prior to 1994 or concurrent cause of neuropathy (diabetes, renal failure, monoclonal gammopathy, etc.). Only cases with clinical signs of distal, symmetric neuropathy and an adequate workup including electrodiagnostic studies were analyzed and categorized as definite, probable, or possible idiopathic neuropathy. Twenty-five controls were randomly chosen per index case. Thirty-five definite, 54 probable, and 77 possible neuropathy cases from the registry (166 total) were found. Nine had been exposed to statins including simvastatin, pravastatin, lovastatin, and fluvastatin. Odds ratios were calculated as 4.6% overall with current users of statins compared to controls and 16.1% with definite neuropathy cases compared to controls. The researchers also calculated an interesting number needed to harm measure and found, based on their odds ratios, 1 excess case of idiopathic peripheral neuropathy for every 2,200 person-years of statin use. Considered in this way, neuropathy was suggested as a more important public health concern than myopathy in patients taking statins. However, potential pitfalls complicate the study, such as whether all symptomatic neuropathy causes were in fact excluded. Examples of complicating disorders include conditions associated with statin use, such as occult diabetes, glucose intolerance, or metabolic syndrome. (Donaghy 2002); however, not all series found a clear association with statins and idiopathic neuropathy (Anderson et al 2005). Despite the rarity of the association, the large number of patients who take these medications makes the association potentially clinically relevant. Further uncertainty was raised in 2007 by the announcement at the meeting of the American Diabetes Association of the large 8-year long Australian Fremantle study of nearly 1300 diabetic patients that demonstrated significantly decreased risk of developing neuropathy in patients treated with statins or fibrates compared to untreated patients. The reduction was 35% and 48%, respectively (Davis et al 2008). Experimental evidence suggests that the statin rosuvastatin improves a mouse model of diabetic neuropathy through improved microcirculation independent of cholesterol lowering effects (Ii et al 2005). The combination of studies and evidence challenges the importance of the earlier Gaist results; statin neuropathy likely occurs but may be much less frequent than recently thought and appears to be neuroprotective in some settings.

One possible case following initiation of simvastatin rapidly developed into neuropathy mimicking Guillain-Barré syndrome; a pravastatin challenge 6 months earlier had led to milder symptoms. The combination suggested a possible hypersensitivity reaction (Rajabally et al 2004). In contrast, lovastatin attenuated nerve injury in an experimental model of experimental allergic neuritis. The effect was blocked by mevalonate (Sarkey et al 2007).

There is no supportive experimental model of the potentially toxic effects, but alteration of membrane function though inhibition of cholesterol synthesis, reduction of axon transport, and inhibition of mitochondrial function have been suggested as possible factors. Interference with selenoprotein synthesis, a well-established pathway also implicated in some hereditary muscle disorders, has been postulated to be causative but probably relates better to myotoxicity. Myopathy from severe selenium deficiency shares some features with statin-induced myopathy (Moosmann and Behl 2004).

Lithium. Lithium has been associated with neuropathy in rare cases. Isolated reports describe the onset of typical toxic neuropathy manifestations after prolonged exposure (Tomasina et al 1990); however, most reports are after acute intoxication or overdose (Brust et al 1979; Uchigata et al 1981; Pamphlett and Mackenzie 1982; Chang et al 1988; Vanhooren et al 1990; Johnston et al 1991; Merwick et al 2011; Chan et al 2012). Excessive levels can occur due, in part, to the narrow therapeutic range of the drug; moreover, neuropathic findings may be underrecognized. Some reported cases are complicated by more generalized toxicity including cerebral impairment with the neuropathy becoming evident only with subsequent recovery. Secondary infections are also problematic, raising the issue of critical illness neuromyopathy in some instances. No convincing experimental evidence is known other than an isolated report suggesting a tendency toward reduced nerve fiber area in rats chronically given lithium over control animals (Licht et al 1997). In fact, in a small series, lithium has been reported to blunt the symptoms of vincristine-associated neuropathy in both mice and humans (Petrini et al 1999). More recently, lithium pretreatment was found to attenuate neuropathy in paclitaxel-treated mice possibly by interacting with paclitaxel-related intracellular calcium signaling pathways (Mo et al 2012).

Phenelzine. Phenelzine is a rarely used monoamine oxidase inhibitor for atypical or refractory depression. Side effects such as hypertensive crises and serious reactions with other agents are well known. Rarely, this agent (but not other MAOIs) has been implicated in inducing peripheral neuropathy. Phenelzine has been shown to affect pyridoxine metabolism and reduce measurable active pyridoxal phosphate levels in humans (Malcolm et al 1994). The compound is in the same chemical class as hydralazine and isoniazid, which both reduce pyridoxal phosphate levels and can cause peripheral neuropathy. Whether this effect is clinically relevant remains to be seen. Malcolm and colleagues demonstrated pyridoxal phosphate levels reduced, on average, by half in 19 patients on phenelzine, but none developed clinical symptoms (Malcolm et al 1994). Several reports of neuropathy associated with phenelzine have been published (Heller and Friedman 1983; Goodheart et al 1991). The neuropathy is described as a typical toxic neuropathy with sensorimotor axonal involvement with predominantly sensory manifestations.

Phenytoin. Peripheral neuropathy from chronic phenytoin use has been long recognized and generally accepted. However, despite many reported patient series, the phenomenon is based on relatively few uncomplicated prospective studies. Most likely, there is a probable effect of protracted use, especially with serum levels chronically higher than 20 µg/ml (in excess of the standard therapeutic range). Peripheral neuropathy was more commonly seen early in the history of phenytoin use when doses of 500 mg/day or higher were not uncommon. However, many of the earlier series had relatively few patients on phenytoin monotherapy, and the contributions of acute reversible phenomena were not taken into account. At current dosages with monitored serum levels, peripheral neuropathy is rare and typically produces only asymptomatic examination findings or minimally discernible neuropathy after many years of therapy. The incidence of neuropathy in epileptics on phenytoin varies considerably depending on patient populations and criteria employed (Lovelace and Horwitz 1968; Eisen et al 1974; Swift et al 1981; Shorvon and Reynolds 1982; Taylor et al 1985). Several variables have been proposed as risk factors for neuropathy development, including supra-therapeutic serum levels (greater than 20 µg/ml), protracted use (less than 10 years), and low folate levels (Lovelace and Horwitz 1968; Eisen et al 1974; Chokroverty and Sayeed 1975; Shorvon and Reynolds 1982). Other series have not found any significant association with phenytoin use compared with other anticonvulsants or these risk factors (Swift et al 1981; Taylor et al 1985). Swift and colleagues found signs of neuropathy in epileptic patients on various therapies and showed a higher incidence among patients on phenobarbital (Swift et al 1981). One case with long-term chronically elevated serum levels (31 to 38.5 µg/ml) had clinically symptomatic neuropathy, and sural nerve biopsy demonstrated mild decreases in large diameter axonal number, axonal shrinkage, and secondary demyelination (Ramirez et al 1986). This patient improved clinically and on electrophysiologic studies subsequent to phenytoin cessation.

In addition, there appears to be separate acute effects on nerve function. Acute exposure to high-dose phenytoin causes reversible slowing of nerve conduction velocity. Phenytoin affects sodium permeability across neuronal membranes by stabilizing inactive sodium channels (Macdonald 1994). Phenytoin in myelinated nerve preparations produces a voltage-dependent block of sodium channels, a shift of the sodium channel inactivation curve to more negative voltages, and a reduced rate of sodium channel recovery from inactivation (Schwarz 1989). However, carbamazepine produced some of these effects as well. Several animal studies have examined the effects of phenytoin on peripheral nerve function. Acute reversible effects have been produced with reduced conduction velocity and compound motor action potentials with acute high dose phenytoin administration in rats (Marcus et al 1981) and slow velocity after several days in guinea pigs (LeQuesne et al 1976). Serum levels were higher than 50 µg/ml. This reversible phenomenon likely represents a physiologic effect but is not a model of long-term toxicity. Some degree of acute reversible effects may have complicated some prior studies that examined chronic toxicity on high dose therapy. A human report has described similar reversible symptomatic effects 3 hours after a phenytoin loading dose (Yoshikawa et al 1999). This may represent an additional acute or subacute idiosyncratic syndrome, but a separate syndrome is not well established. The acute reversible effects on nerve function are well established, but the chronic neuropathy is considered a probable association (Mann et al 2000).

Proton pump inhibitors. A rare effect of commonly used medications can be particularly problematic to resolve and substantiate. One example is the proton pump inhibitors omeprazole and lansoprazole. Rajabally and Jacob reported a 42-year-old woman who developed predominantly sensory neuropathy after 3 months of lansoprazole use (Rajabally and Jacob 2005). Some partial improvement was noted after later stopping the medication, and no worsening was seen after switching to rabeprazole and then to ranitidine. Three other cases are reported with omeprazole, 2 of which have adequate electrophysiology and clinical information (Faucheux et al 1998). Additional carefully studied examples are needed to further substantiate this possible link with medication-induced neuropathy in this widely used class of medications. No new cases have been published as of the most recent literature search since these reports despite continued widespread use of these agents. However, these agents and histamine-2 blockers may affect vitamin B12 absorption and lead to secondary neurologic complications (Lam et al 2013).

Slaughterhouse workers progressive inflammatory neuropathy.
Although not technically a medication-induced neuropathy, this local toxic epidemic at several pork processing plants in Minnesota and surrounding states produced considerable activity and investigation by numerous researchers, mostly at the Centers for Disease Control (Centers for Disease Control and Prevention (CDC) 2008). Twelve workers in a swine slaughterhouse in Minnesota developed a progressive inflammatory neuropathy with symptoms ranging from acute paralysis to gradually progressive symmetric weakness predominantly in the legs from 8 to 213 days with varying severity between November 2006 and 2007. Eleven patients had evidence of axonal or demyelinating features by electrodiagnostic testing. Spinal fluid from 7 patients showed elevated protein (mean 120 mg/dl) with no or minimal pleocytosis. Ten patients had evidence of inflammation on spinal magnetic resonance imaging (9 patients in peripheral nerves or roots and 1 patient in the anterior spinal cord). Three patients with sural nerve biopsy showed mild perivascular inflammation. In summary, patients were characterized with a sensory greater than motor polyradiculopathy, predominantly at the root or distal nerve level. The CDC researchers identified that all patients were working in close proximity to swine heads. A compressed air device used to liquefy porcine brain material may have generated aerosolized brain material, which may have induced an immune neurotoxic response. Ultimately work at the Mayo Clinic led by Vanda Lennon found a complex autoantibody profile dominated by neural cation channel IgGs that most significantly affected voltage-gated potassium channels (Meeusen et al 2012).

Tacrolimus. Prograf, previously known as FK-506, is a novel immunosuppressant that is widely used in transplant medicine and for suppression of some inflammatory disorders. The agent is a macrolide antibiotic that suppresses both cellular and humoral mediated immune responses. Neurotoxicity is common in treated patients, in part, because of the relatively high doses usually given. Central toxicity is more common with a variety of findings including leukoencephalopathy, seizures, behavioral changes, headache, or other cortical signs, many of which are dose dependent. Peripheral neuropathy appears to take the form of a severe multifocal demyelinating neuropathy that resembles chronic inflammatory demyelinating neuropathy (Wilson et al 1994; Bronster et al 1995; Labate et al 2010). Patients have responded to IVIG or plasmapheresis as well.

Both cyclosporin A and tacrolimus act through inhibition of calcineurin, though by different means (tacrolimus binding protein: FKBP-12) (Snyder et al 1998). The calcineurin inhibition, through several steps, decreases IL-2 and eventually T-cell proliferation. This pathway is also the likely cause of much of the central neurotoxicity and possibly the peripheral effects. Tacrolimus also has an additional separate function through a different binding protein, FKBP-52, that acts as a nerve stimulator, increases growth associated protein (GAP-43), and is beneficial to nerve regeneration in nerve axotomy and ischemia models (Gold et al 1998; Kihara et al 2001). FKBP-52 is part of a steroid receptor complex and may represent a target for future regenerative therapies separate from the growth factor and Trk pathways. The mechanism of why, in some patients, an immune attack that resembles chronic inflammatory demyelinating neuropathy or other autoimmune neuropathy is unclear; however, the number of reported examples is small. Interestingly, tacrolimus has also been shown to have significant and potentially therapeutic neuroregenerative activity, possibly derived from a separate pathway from the immunosuppressive calcineurin inhibition--FKBP-52 binding protein (Kvist et al 2003; Gold et al 2004). Schwann cells may play an important intermediary role (Birge et al 2004). A similar agent, sirolimus, appears to have less risk of this reaction but at least 1 case is reported (Bilodeau et al 2008).

Tumor necrosis factor-alpha blockers. Tumor necrosis factor-alpha (TNF-alpha) blockers are used in the treatment of various forms of inflammatory arthritis and inflammatory bowel diseases but are also associated with inducing or worsening other autoimmune disorders including multiple sclerosis (Stubgen 2008). One agent (etanercept) has been reported to improve chronic inflammatory demyelinating neuropathy (CIDP) (Latov and Sherman 2000; Chin et al 2003). Postmarketing reporting identified 15 patients diagnosed with Guillain-Barré syndrome or Miller Fisher syndrome from 6 weeks to 2 years after starting a TNF-alpha blocker, although associated infection may be a more important risk factor (Robinson et al 2001; Shin et al 2006). One case developed acute sensorimotor neuropathy and concomitant encephalopathy (Faivre et al 2010). Richez and colleagues reported 2 cases that developed a CIDP-like illness (Richez et al 2005). One treated with etanercept for rheumatoid arthritis developed a demyelinating neuropathy 17 months later. The other received infliximab for ankylosing spondylitis and developed CIDP 3 months later. Both incompletely improved after drug cessation without specific treatment for CIDP. Infliximab is also associated with several other CIDP-like cases with underlying rheumatoid arthritis (Jarand et al 2006; Tektonidou et al 2007; Alshekhlee et al 2010) and 3 cases with underlying psoriatic arthritis, a condition which is much less likely to induce spontaneous or vasculitic neuropathy (Stubgen 2008; Eguren et al 2009). Numerous cases resembling multifocal motor neuropathy are also reported in association with infliximab (Singer 2004; Cocito et al 2005; Rodriguez-Escalera et al 2005; Paolazzi et al 2009). However, others question whether some of these cases were actually a form of vasculitic mononeuritis multiplex triggered by the infliximab (Birnbaum 2007). One case of proposed infliximab-associated immune-mediated sensory polyradiculopathy was successfully treated with intravenous gammaglobulin (Naruse et al 2013). There are additional less clear associations with mononeuropathy and axonal sensory or sensorimotor neuropathy (Jarand et al 2006). In any event, it seems that infliximab and etanercept can contribute to or trigger an immune-mediated neuropathy in some possibly susceptible patients (Kotyla et al 2007). Adalimumab is not clearly associated with chronic neuropathy but was associated with one possible Guillain-Barré syndrome case. Ipilimumab, a monoclonal antibody that is not a TNF alpha antagonist but instead blocks a natural inhibitor of cytotoxic T-cell response to cancer cells, is approved to treat melanoma and is undergoing trials for other cancer types. A case of acute neuropathy mimicking Guillain-Barré syndrome is reported; acute enteric neuropathy is also recognized (Gaudy et al 2013).

Interestingly, in light of the fluoroquinolone story discussed earlier, peripheral neuropathy associated with TNF-alpha agents was the most common adverse neurologic event reported to the Food and Drug Administration Adverse Event Reporting System (296 reports, 38.3%), exceeding central nervous system and/or spinal cord demyelination (153 reports, 19.8%) (Deepak et al 2013). The majority of reports (71%) were labeled as “possibly associated” and not higher grades of certainty.

In contrast, these agents may have other protective properties. A mouse model of bortezomib neuropathy found that upregulation of TNF-alpha was neuroprotective, possibly by limiting certain inflammatory cytokines (Ale et al 2014).

Zimeldine. Zimeldine is another agent never approved for use in the United States but available transiently as an antidepressant in Sweden, functioning as a 5-HT reuptake inhibitor with purported fewer side effects. The drug is best known as a probable precipitating factor of an outbreak of Guillain-Barré syndrome in Sweden in 1983. The drug was withdrawn from the market 18 months after introduction because of this outbreak. A subsequent Bayesian analysis concluded that the association was supported by relevant data (Naranjo et al 1990). No additional cases, however, were identified in a retrospective review of 761 patients on zimeldine reported more recently from the same region (Bengtsson et al 1994). Hypersensitivity reactions are relatively common with this agent (1.4% to 13%), raising the question of potential immune-mediated mechanisms in this phenomenon. Zimeldine appears to affect T-cell function and blunt experimental allergic neuritis in a rat model of Guillain-Barré syndrome (Bengtsson et al 1992). The risk of developing Guillain-Barré syndrome from zimeldine was estimated as increased 25-fold compared to natural incidence controls (Fagius et al 1985).

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