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.

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.

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.

Quantitative sensory testing demonstrates that subclinical sensory neuropathy is prevalent in patients with cancer.

Vibration threshold (VT) determinations were used to assess the function of the large nerve-fiber sensory system in 171 patients with cancer and 58 healthy subjects. Significant differences in VT indicate dysfunction of this sensory system in the cancer group. Twelve percent of the cancer patients had elevated VT compared with 1.7% of control subjects. Elevated VT was not associated with risk factors for neuropathy such as diabetes, renal disease, poor nutrition, or treatment with chemotherapy. Although VT elevation was associated with alcoholism and increasing age, these variables accounted for only a small proportion of the variance in VT. These data suggest that VT determinations are a useful method for quantifying sensory abnormalities in cancer patients. Sensory abnormalities occur in a significant proportion of patients with cancer and seem to be related directly to the neoplasm, rather than to known risk factors for neuropathy.

Relapsing ophthalmoparesis-sensory neuropathy syndrome.

We studied two patients with recurrent sensory neuropathy and weakness of extraocular muscles. There was electrophysiologic evidence of multifocal demyelination of sensory nerves, with relative sparing of somatic motor nerves. Sural nerve biopsy in one patient showed segmental demyelination. We believe that these patients had an unusual form of inflammatory polyneuropathy--possibly a relapsing variant of the Miller-Fisher syndrome of acute idiopathic polyneuritis.

Rapid screening for peripheral neuropathy: a field study with the Optacon.

The modified Optacon, a simple battery-powered device that measures fingertip vibration sensation, was used by para-professionals to screen 257 acrylamide-exposed individuals. Consistent data were obtained on repeated testing of individuals, and there was an age-related linear decrease in vibration sensitivity within the population. Subclinical peripheral neuropathy was detected in two individuals, one acrylamide-related and the other nutritional-alcoholic. This study establishes the use of the modified Optacon as a screening device for some types of peripheral nerve dysfunction.

The acute sensory neuronopathy syndrome: a distinct clinical entity.

Four to twelve days following initial antibiotic treatment for a febrile illness, three adults suddenly experienced numbness and pain over the face and entire body. Each had received a penicillin or a semisynthetic derivative, and two patients also received other antibiotics. Signs appeared rapidly and included profound sensory ataxia, areflexia, and widespread sensory loss, primarily of large fiber modalities (proprioceptive sensibility). Slowed or absent sensory conduction was found. There was no weakness, and electrical study of muscle and motor nerve conduction was normal in all. The cerebrospinal fluid was acellular, and protein levels were elevated to 126 and 175 mg/dl in two cases and were normal in the other. Presently, all have a severe, static, residual sensory deficit. During follow-up of five years, no evidence of neoplastic disease or immunological disorder has appeared. Because of the rapid onset, widespread and pure sensory involvement, and poor recovery, the lesion is most likely confined to the dorsal root and gasserian ganglia (sensory neuronopathy). This pattern resembles that of the experimental lesions induced by doxorubicin and pyridoxine. It appears likely that either the previously administered antibiotics or the illness for which they were administered were of pathogenetic importance. We designate this previously unrecognized disorder the acute sensory neuronopathy syndrome and suggest that it represents a distinct, readily identifiable clinical entity.

Isolation and characterization of glial filaments from human brain.

Intermediate (8--9 nm) filaments of human central nervous system astrocytes were isolated from the gliosed white matter of cases of adrenoleukodystrophy (ALD). This hereditary lipidosis is characterized pathologically by demyelination, loss of axons, and replacement of the white matter of the caudal cerebrum by a glial scar. Glial filaments were composed largely of a single protein component with a mol wt of about 49,000 daltons. Smaller components (44,000--39,000 daltons) were detected in some samples, and appear to represent degradation products of the filament protein. Human neurofilaments were isolated from the normal frontal white matter of ALD cases by the standard myelin-free axon technique. Isolated glial and neurofilament proteins comigrated during acrylamide gel electrophoresis in SDS. Polypeptides resulting from cyanogen bromide cleavage of the two filament proteins were the same. Both proteins reacted with rabbit antisera raised against isolated bovine neurofilament protein and human glial fibrillary acidic protein.

Ultrastructural studies of the dying-back process. IV. Differential vulnerability of PNS and CNS fibers in experimental central-peripheral distal axonopathies.

A companion paper in this issue (46) described the evolution of peripheral nervous system dying-back disease of the giant axonal type in animals chronically intoxicated with the neurotoxic hexacarbons n-hexane (CH3CH2CH2CH2CH2CH3), methyl n-butyl ketone or MBK (CH3COCH2CH2CH2CH3), and 2,5-hexanedione (CH3COCH2CH2COCH3). The present study compares the distribution and pattern of peripheral (PNS) and central nervous system (CNS) dying-back disease produced by these three neurotoxic hexacarbons with that produced by acrylamide (CH2CHCONH2), and, in addition, employs these compounds to address unresolved issues in the dying-back process. In the PNS, large myelinated fibers in tibial nerve branches supplying calf muscles were especially sensitive in rats intoxicated with hexacarbons. These nerve branches and sensory plantar nerves in the hindfeet were equally vulnerable in acrylamide-treated rats. In both conditions, fibers located at these sites commenced degeneration before the distal regions of much longer and smaller diameter nerve fibers in nerve branches supplying the flexor digitorum brevis muscle and, in rats intoxicated with hexacarbons, before equivalent regions of plantar sensory branches to the digits. Pacinian corpuscles sited in the hindfeet of intoxicated cats were much less vulnerable to MBK than to acrylamide. Rats and cats intoxicated with hexacarbons displayed giant axonal swellings in vulnerable regions of the PNS degeneration in these animals was accompanied by pronounced endoneurial edema. In the CNS, rostral regions of long, ascending tracts (dorso-spino-cerebellar, gracile and, later, the cuneate) and the caudal end of long, descending tracts (lateral colums, ventrolateral and ventromedial tracts) of hexacarbon-treated animals were especially vulnerable. After prolonged intoxication of cats with MBK, giant axonal swelling was also found in preterminal and terminal axons in Rexed laminae V-VII at spinal levels C4 through S3-Neurofilament proliferation without giant axonal swelling was seen in CNS fibers of rats intoxicated with acrylamide. Taken in concert, the findings underline the importance of axon diameter and length in determining the hierarchy of fiber vulnerability and indicate the common sensitivity of selected regions of the PNS and CNS. The term central-peripheral distal axonopathy is introduced to emphasize the widespread, distal distribution of disease in these and in similar experimental conditions. It is suggested that certain human neuropathies (toxic, nutritional, uremic, diabetic and some hereditary polyneuropathies, and the neuropathy associated with multiple myeloma) are additional examples of central-peripheral distal axonopathies.

Histochemical characteristics of the striated inclusions of adrenoleukodystrophy.

The straited accumulations in adrenal cortical cells and brain macrophages that are characteristic of adrenoleukodystrophy have been studied histochemically in cryostat sections to seek leads for the biochemical identification of the striated material. It stained pale pink with oil red O and did not stain with the Schultz cholesterol procedure or periodic acid-Schiff technique. By utilizing the birefringence of the accumulations as a marker, it was determined that, unlike natural cholesterol and cholesterol esters, the striated material was resistant to acetone and ethanol extraction. It was readily soluble, however, in nonpolar solvents such as n-hexane and chloroform. These findings indicated that the material was most probably a lipid, and they suggested that sequential extraction of adrenoleukodystrophy adrenal and brain with acetone and then n-hexane could be used to isolate this material in relatively pure form. Based on this lead, biochemical studies have just revealed a fatty acid abnormality in adrenoleukodystrophy which appears to be unique to this genetic disease.

Adrenoleukodystrophy. A clinical and pathological study of 17 cases.

Adrenoleukodystrophy was diagnosed pathologically in 17 male patients. The diagnosis was suggested by clinical and laboratory signs of primary adrenal failure and by neurological signs referable to the degeneration of white matter. Neurological findings usually predominated over clinical stigmata of adrenal failure. Adrenal biopsy has proved to be the most reliable diagnostic test, while brain biopsy has often been misleading. The histological picture of the brain lesion differs substantially from that of the adrenal, but the presence of similar ultrastructural cytoplasmic inclusions suggests a common metabolic disorder. Morphological analysis of the cerebral lesion indicates that the destruction may spread in a caudal-rostral direction. The intense inflammatory cell response occurs within the demyelinated areas, behing the area of active myelin breakdown, and appears to be a secondary feature of white matter degeneration.

Intranuclear "paramyxovirus-like" material in multiple sclerosis, adreno-leukodystrophy and Kuf's disease.

Detailed comparative ultrastructural examination of multiple sclerosis (MS) plaques, inflammatory CNS lesions from adreno-leukodystrophy(A-LD), tissue from a case of chronic granulomatous meningitis, biopsy samples of necrotic cerebral cortex and CNS tissue from a case of Kuf's disease (adult-type ceroid lipofuscinosis), has revealed that the intranuclear filamentous material previously thought to be related to a viral infection in MS is a non-specific finding. These intranuclear strands were, however, found in greatest frequency in the acute lesions of MS and were absent from chronically demyelinated areas. The macrophages, lymphocytes and fibrocytes containing filamentous material in the nuclei were mainly perivascular. In A-LD, some macrophages in active lesions contained similar nuclei, and in Kuf's disease they were present in some glial cells in the cerebral cortex.

Adreno-leukodystrophy (sex-linked Schilder's disease). A pathogenetic hypothesis based on ultrastructural lesions in adrenal cortex, peripheral nerve and testis.

Striated adrenal cells in the zona reticularis and inner fasciculata apparently constitute the initial adrenolytic lesion in patients with adreno-leukodystrophy (ALD). Cytoplasmic ballooning and macrovacuolization develop after the striations, and probably represent exaggerated responses to adrenocorticotropin (ACTH). Intracytoplasmic lamellae and lamellar-lipid profiles, containing a free 3beta-hydroxysterol, are the ultrastructural correlates of the striations seen with the light microscope. The ultrastructural demonstration of intracytoplasmic lamellae and lamellar-lipid profiles in adrenal striated cells, testicular interstitial cells, Schwann cells and brain macrophages from patients with ALD provides further morphologic evidence for a systemic metabolic defect common to the nervous and endocrine systems. In our experience, adrenal biopsy has proven to be the most effective procedure for the diagnosis of adreno-leukodystrophy. An hypothesis proposing a membrane abnormality affecting its stability and turnover might explain the concomitant destruction of adrenal cortex and brain in these patients.