Peripheral neuropathy in young-old and old-old patients.

Diabetes is said to account for most cases of neuropathy in the elderly. We reviewed records of 223 young-old (65-79 years) and 77 old-old (>or=80 years) patients referred for evaluation of neuropathic symptoms over a 9-year period. We prospectively validated our findings in 102 consecutive elderly (77 young-old) patients receiving intensive evaluation for neuropathy. Diabetes was the most common cause of neuropathy (41%), but was less common in the old-old (25% versus 46%, P < 0.001). Idiopathic neuropathies were more common in the old-old (39% versus 9%, P < 0.001). Alcoholic and nutritional neuropathies were uncommon in the old-old. Electrophysiological studies showed that most patients had an axonal type of neuropathy. Sural and peroneal response amplitudes were poorly correlated with age. We obtained similar results in our prospective study. The distribution of causes of neuropathies in young-old and old-old patients, in a hospital-based sample, is age-related. Future studies need to include the old-old to better understand the nature of neuropathy in the elderly.

Classification of neurotoxic responses based on vulnerability of cellular sites.

An ideal classification of neurotoxic substances should link the vulnerable target of chemical attack to alterations in neural function. There is little basis for classifying agents based on their common use or physico-chemical properties. Outlined in this article are the principal cellular targets of substances that perturb the nervous system structure and function.

Occupational exposure to methyl isobutyl ketone causes lasting impairment in working memory.

The authors describe serial evaluations of a 44-year-old man who became cognitively impaired during a 6-year period of repeated exposure to high levels of methyl isobutyl ketone (MIBK). Neuropsychological tests administered six times over 10 years demonstrated a stable pattern of cognitive impairment. Dynamic imaging studies suggested persistent CNS dysfunction. The authors conclude that chronic, high-level, occupational MIBK exposure can cause a persistent cognitive syndrome best explained by impaired working memory.

Prevalence of peripheral neuropathy in injection drug users.

BACKGROUND: Nucleoside analogue reverse transcriptase inhibitors are a critical component of antiretroviral therapy in HIV-infected persons. Several of these medications cause painful, dose-limiting peripheral neuropathy (PN), which may develop earlier and more intensely in persons with preexisting neuropathy. The prevalence of baseline peripheral neuropathy in injection drug users (IDUs), one of the largest populations of HIV-infected persons, has not been described, yet has important implications for the selection of antiretroviral therapy. METHODS: The authors performed a cross-sectional study of PN in 212 HIV-seronegative and HIV-seropositive IDUs using detailed neurologic histories, physical examinations, quantitative electrophysiologic study, and quantitative sensory testing. Data were used to assign patients to one of four positive categories of PN or one of two negative categories. RESULTS: PN was present in 24.5% of HIV-seronegative IDUs, three to four times the reported frequency for HIV-seronegative persons in the general or male homosexual population. PN was present in 32.1% of HIV-seropositive patients. PN was axonal in nature and associated with increased age and alcohol use. PN was asymptomatic in 81% of HIV-seronegative and 71% of HIV-seropositive patients with PN. CONCLUSIONS: There is a high prevalence of PN in HIV-seronegative IDUs. Although these PNs do not seem to predispose HIV-seropositive IDUs to HIV-related PN, they may increase the likelihood of iatrogenic neuropathy. Intravenous drug users may need more diligent monitoring when administered nucleoside analogues than patients in risk groups with lower endemic rates of PN.

Sensory neuropathy associated with Dursban (chlorpyrifos) exposure.

Chlorpyrifos (Dursban) is an organophosphate insecticide with extensive domestic and agricultural applications. It is regarded as safe for these purposes; one report of neurotoxicity is attributed to massive ingestion in a suicide attempt. We report eight people who developed peripheral neuropathy after exposure to exterminator-applied commercial Dursban; five also experienced memory loss and cognitive slowing. Evaluation failed to reveal other causes of neurologic dysfunction; symptoms recurred in one patient following accidental reexposure. We conclude that environmental contact with chlorpyrifos can cause sensory neuropathy and CNS dysfunction and that this agent should be used with caution.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

2',3'-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients.

We administered the antiviral agent 2',3'-dideoxycytidine (ddC) to HIV-infected patients with either ARC or AIDS as part of the AIDS Clinical Treatment Group protocol 012 and serially evaluated them with neuropathic symptom questionnaires, neurologic examinations, nerve conduction studies, and quantitative sensory testing (QST). All patients treated with high-dose ddC (0.06 and 0.03 mg/kg every 4 hours) developed a painful, predominantly sensory peripheral neuropathy, with a mean onset of 7.7 weeks, which reached severe intensity over several days. Abnormalities of vibration QST threshold preceded clinical symptoms. Treatment with 0.01 mg/kg every 4 hours produced a similar neuropathy, although of milder severity, later onset (mean, 9.3 weeks), and slower progression. In these patients, the onset of clinical symptoms and QST abnormalities were coincident. Only two of six patients treated with 0.005 mg/kg every 4 hours developed clinical or laboratory evidence of neuropathy; in both cases it was very mild and delayed in onset (26 weeks). All patients treated with high-dose ddC reported progression of symptoms (coasting) for 2 to 3 weeks following discontinuation of therapy. This study documents a painful sensory neuropathy resulting from treatment with ddC. With high-dose treatment, only the rapidity of onset and progression differentiated it from the distal, predominantly sensory neuropathy of AIDS.

Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity.

We administered either 1 or 3 g/d of pyridoxine (vitamin B6) to five healthy volunteers and repeatedly followed serum pyridoxal phosphate levels, clinical symptoms and signs, quantitative sensory thresholds (QSTs), and sural nerve electrophysiology. Pyridoxine was discontinued at the first sign of either clinical or laboratory abnormality. In all subjects, sensory symptoms and QST abnormalities occurred concurrently. Subjects receiving higher doses became symptomatic earlier than low-dose subjects. Elevation of thermal QSTs preceded or exceeded that for vibration in the three low-dose subjects; vibration and thermal QST became abnormal simultaneously in the higher-dose subjects. A reduction in the amplitude of the sural sensory potential lagged behind QST changes in two of three subjects. Symptoms continued to progress ("coasting") for 2 to 3 weeks despite stopping pyridoxine administration and the return of serum pyridoxal phosphate levels to normal. This study suggests that (1) there is a clear dose-percent relationship for pyridoxine-induced neuropathy, (2) QST is a sensitive measurement for detecting early peripheral neuropathy; QST abnormalities may precede changes in nerve conduction studies, (3) coasting appears unrelated to persistently elevated blood levels of the toxin, and (4) a dose-dependent vulnerability may exist among nerve fibers of different caliber when exposed to an axonal toxin, such as pyridoxine.

Invited review: peripheral neuropathy in Sjogren's syndrome.

Our experience and review of the literature reveal that Sjogren's syndrome (SS) is an important, poorly recognized cause of peripheral neuropathy. Several forms of peripheral nerve dysfunction occur in SS including trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensory neuropathy, distal sensorimotor peripheral neuropathy and a pure sensory neuronopathy syndrome. Rarely, chronic relapsing inflammatory polyneuropathy and multiple cranial neuropathies appear. Clinical evidence of glandular involvement is often minimal or absent when patients with SS develop peripheral neuropathy; and the diagnosis of the underlying condition is elusive. We review clinical and laboratory features of this disorder and suggest appropriate evaluation of patients with neuropathy and suspected SS.

Delayed onset of distal axonal neuropathy in primates after prolonged low-level administration of a neurotoxin.

Short-latency somatosensory evoked potentials were recorded from surface electrodes overlying peripheral nerve, spinal cord, and cortex in 4 monkeys during prolonged intoxication with low levels of acrylamide. A fifth animal served as a longitudinal control subject. Slowing of the response across the spinal-medullary junction was a reliable sign, manifest only after prolonged exposure. Associated morphological changes were preterminal accumulation of axonal neurofilaments without synaptic disruption in the gracile nucleus. The induced alterations in the latency of short-latency somatosensory evoked potentials and in axon morphology were reversible after 7 months of recovery. The extreme delay in onset of subtle neurological dysfunction (940 days) following administration of a presumed safe level of acrylamide suggests that permissible levels of human exposure to toxins of this type should be reassessed.

Taxol produces a predominantly sensory neuropathy.

Taxol, a plant alkaloid with promise as an antineoplastic agent, produced a predominantly sensory neuropathy in 16 of 60 patients treated in two phase I trials. This neuropathy occurred only at taxol doses greater than 200 mg/m2. Symptoms typically started 1 to 3 days following treatment, beginning in the hands and feet simultaneously in most patients. Electrophysiologic data suggests both axonal degeneration and demyelination. This previously undefined neurotoxic neuropathy most likely results from taxol's unique ability to produce microtubule aggregation in dorsal root ganglion cells, axons, and Schwann cells.

Central nervous system effects of chronic toluene abuse--clinical, brainstem evoked response and magnetic resonance imaging studies.

We describe the results of neurological evaluation, magnetic resonance imaging (MRI) of the brain and brainstem auditory evoked response (BAER) testing in 11 chronic toluene vapor abusers. Neurological abnormalities were seen in four of 11 individuals and included cognitive, pyramidal, cerebellar and brainstem findings. MRI of the brain was abnormal in three of 11 individuals and revealed the following abnormalities: 1) Diffuse cerebral, cerebellar, and brainstem atrophy; 2) Loss of differentiation between the gray and white matter throughout the CNS; and 3) Increased periventricular white matter signal intensity on T2 weighted images. BAERs were abnormal (control mean +/- 3 S.D.) in five of 11 individuals. As a group, the latency of V (p less than 0.01), the III-V interpeak (p less than 0.05) and the I-V interpeak latencies were prolonged compared to controls. All three individuals with abnormal MRI scans also had abnormal neurological examinations and BAERs. Two of five individuals with abnormal BAERs, however, had normal neurological examinations and MRI scans. Our data support previous findings of diffuse white matter involvement in chronic toluene abusers and suggest that BAERs may detect early CNS injury from toluene inhalation even at a time when neurological examination and MRI scans are normal. BAERs, therefore, may be a sensitive screening test to monitor individuals at risk from toluene exposure (either abusers or industrially exposed individuals) for early evidence of CNS injury.

Cognitive impairment and sensory loss associated with chronic low-level ethylene oxide exposure.

A 29-year-old college graduate worked for 10 years adjacent to an ethylene oxide (EtO) chemical sterilizer. When the sterilizer was closed, levels of EtO in the air around the sterilizer were 4.2 ppm (OSHA maximum level, 1 ppm). Seven years after beginning work with EtO, she experienced impaired memory, increased irritability, clumsiness, and falling. Three years later exposure ceased, and symptoms markedly improved over the next few months, but did not disappear entirely. Neurologic and neuropsychological exams 1 year after exposure ceased demonstrated emotional lability, impaired concentration, cognitive slowing, impaired recent and remote memory, and impaired thermal and vibratory sense in distal limbs. Her pattern of relatively preserved learning and profound forgetting distinguished her from most other subjects with memory disorders. No other causes for the condition were identified.

Studies on the etiology and pathogenesis of motor neuron diseases. II. Clinical and electrophysiologic features of pyramidal dysfunction in macaques fed Lathyrus sativus and IDPN.

A primate model of lathyrism has been produced in well-nourished male cynomolgus monkeys chronically fed a fortified diet composed of Lathyrus sativus (chickling or grass pea) and given daily per os an alcoholic extract of this legume. Animals given a diet of non-neurotoxic Cicer arietinum (chick pea) cross-matched with the nutritional properties of the experimental diet served as controls. Another group of animals received the same diet and oral doses of beta, beta'-iminodipropionitrile (IDPN), a reference compound that has been termed an "experimental neurolathyrogen." Monkeys fed Lathyrus developed clinical and electrophysiologic evidence of corticospinal deficits after 3 to 10 months of feeding. Animals administered IDPN showed clinical and/or electrophysiologic changes in the PNS and CNS motor and sensory pathways, and signs of cerebellar dysfunction. Since the two primate disorders are separable on clinical and electrophysiologic grounds, further use of the term "experimental neurolathyrogen" to describe the neurotoxic properties of IDPN seems inappropriate. These findings demonstrate the feasibility of developing a model of early human lathyrism in adequately nourished nonhuman primates.