Cyanides

Cyanides

sCJD. Hyperintensity of the basal ganglia in T2-weighted images is characteristic. Emerging, and more sensitive, techniques such as FLAIR (fluid-attenuated inversion recovery) and DWI have demonstrated cortical signal increase, thus increasing overall MRI sensitivity and specificity in specialized centers to over 90%.

Treatment The first drug studies of CJD were undertaken almost 40 years ago and since then dozens of drugs have been tested. Yet no effective treatment has been found. Nevertheless four compounds have been (or are currently being) studied with sufficient rigor and in an adequate number of patients. Quinacrine, once widely used antimalarial drug, was found to block formation of PrPSc in infected cell cultures. A recent patient-preference trial on all forms of CJD showed acceptable level of tolerance but no effect on the clinical course of CJD. Flupirtine maleate, a centrally acting nonopioid analgesic, has been tested in a randomized double-blind study of subjects with the diagnosis of probable CJD. Treated patients showed a significantly slower rate of cognitive deterioration but no significant difference in survival time. Administration of doxycycline, a member of the tetracycline group, to sCJD patients under compassionate treatment has been reported to more than double survival compared to untreated sCJD subjects. A phase II, multicenter, randomized, doubleblind study is ongoing.

Acknowledgments Our most heartfelt thanks go to the families of the CJD patients that made this review possible. The authors also want to thank Dr. Miyuki Shimoji for preparing Figure 1. Supported by NIA AG-14359, NIH R01 NS062787, CJD Foundation, New Diagnostic Methods, CDC UR8/ CCU515004, and the Charles S. Britton Fund.

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See also: Ataxia; Electroencephalography (EEG); Kuru; Myoclonus; Variant Creutzfeldt–Jakob Disease.

Further Reading Aguzzi A, Sigurdson C, and Heikenwaelder M (2008) Molecular mechanisms of prion pathogenesis. Annual Review of Pathology 3: 11–40. Cali I, et al. (2006) Classification of sporadic Creutzfeldt–Jakob disease revisited. Brain 129(Pt 9): 2266–2277. Cali I, et al. (2009) Co-existence of PrPSc type 1 and 2 in sporadic Creutzfeldt–Jakob disease: Its effect on the phenotype and prion type characteristics. Brain (in press). Castellani RJ, et al. (2004) Sensitivity of 14–3–3 protein test varies in subtypes of sporadic Creutzfeldt–Jakob disease. Neurology 63(3): 436–442. Gambetti P, Kong Q, Zou W, Parchi P, and Chen SG (2003) Sporadic and familial CJD: Classification and characterization. British Medical Bulletin 66: 213–239. Gibbs CJ Jr, et al. (1968) Creutzfeldt–Jakob disease (spongiform encephalopathy): Transmission to the chimpanzee. Science 161 (839): 388–389. Historical reflections. In: Prusiner SB, Collinge J, Powell J, and Anderton B (eds.) (1992) Prion Diseases of Humans and Animals, pp. 15–91. Chichester, West Sussex UK: Ellis Horwood. Krasnianski A, et al. (2008) MRI in the classical MM1 and the atypical MV2 subtypes of sporadic CJD: An inter-observer agreement study. European Journal of Neurology 15(8): 762–771. Linden R, et al. (2008) Physiology of the prion protein. Physiological Reviews 88(2): 673–728. Meggendorfer F (1930) Klinische und genealogische Beobachtungen bei einem Fall von spastischer Pseudosklerose. Zeitschrift fu¨r die gesamte Neurologie und Psychiatrie 128: 337–341. Monari L, et al. (1994) Fatal familial insomnia and familial Creutzfeldt–Jakob disease: different prion proteins determined by a DNA polymorphism. Proceedings of the National Academy of Sciences of the United State of America 91(7): 2839–2842. Parchi P, et al. (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Annals of Neurology 39(6): 767–778. Parchi P, et al. (1999) Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Annals of Neurology 46(2): 224–233. Parchi P, et al. (1997) Typing prion isoforms. Nature 386(6622): 232–234. Parchi P, et al. (2000) Genetic influence on the structural variations of the abnormal prion protein. Proceedings of the National Academy of Sciences of the United States of America 97(18): 10168–10172. Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216(4542): 136–144. Triarhou LC (2009) Alfons Maria Jakob (1884–1931), neuropathologist par excellence. Scientific endeavors in Europe and the Americas. European Neurology 61(1): 52–58. Epub 2008 Nov 25.

Cyanides C G Goetz, Rush University Medical Center, Chicago, IL, USA ã 2010 Elsevier Ltd. All rights reserved.

Chemistry and Exposure Information Hydrocyanic acid is one of the most rapidly acting poisons, and it is therefore used especially as a suicidal or homicidal agent. Cyanide intoxication also occurs

accidentally during fumigation, including fire inhalation, electroplating, and gold or silver ore extraction. Free hydrocyanic acid or cyanogenetic glycosides are produced by choke–cherry trees and other plants, and accidental poisoning is due to the ingestion and chewing of the toxic

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Cyanides

seeds. Cyanides are general protoplasmic poisons producing asphyxia by inhibiting the action of energy-generating respiratory enzymes throughout the body. Benzyl cyanides inhibit dopamine beta hydroxylase, the synthetic enzyme for the neurochemical, norepinephrine. They also induce a brief stimulation of the central nervous system that is rapidly replaced by a paralyzing action. In addition, cyanides interact with the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL), to generate a biologically active compound (cyanohydrin adduct) that may contribute to its neurotoxicity.

Clinical Signs of Intoxication Within 10 min of the ingestion of lethal doses of cyanide, victims lose consciousness, exhibit generalized convulsions, and die within 2–5 min. Most often, the toxic effects appear more slowly with some agitation, salivation, anxiety, confusion, and nausea. These symptoms are accompanied by vertigo, headache, unsteady gait, and a feeling of stiffness in the lower extremities. Seizures may develop and appear to relate to a depletion of the energy generating compound, adenosine triphosphate (ATP). Breathing is stentorian; the face is flushed and then cyanotic; and the pupils are dilated. Respiration frequently ceases before the heart stops, and death usually ensues within 15 min to 1 h. Recovery may occur when treatment is instituted rapidly. If patients survive the first hour, they usually recover completely, although some experience weakness, unsteady gait, headache, difficulty in speaking, and drowsiness. There is a high degree of individual susceptibility to cyanide intoxication, but some patients have survived even after the ingestion of 6 g of potassium cyanide, although as little as 0.13 g can be lethal. After the inhalation of gaseous hydrocyanic acid, the victim develops nausea, vomiting, and difficulty in breathing. Unconsciousness supervenes, and within 10 min, respiratory failure and death may occur. Survivors typically have parkinsonian features, with masked facial expression, severe hypophonia, bradykinesia of limbs and trunk, and unsteady gait due to postural reflex compromise. Tremor is not always present and can have a mixed rest/postural/kinetic character. Some patients have additional cognitive alterations and some have added cerebellar features of poor coordination and slurred speech, which superimpose on parkinsonian hypophonia. MR scans show damage to the globus pallidus, putamen, midbrain, and cerebellum. The evidence of hemorrhagic necrosis develops within 6 weeks of intoxication and cystic degeneration is a late finding. The sensorimotor cortex can also be involved in pseudolaminar necrosis. 18Ffluoro-dopa positron emission tomography scans can reveal a symmetrical reduction of activity in two anatomical areas, the caudate nucleus and putamen. Glucose

metabolism scans show regional reductions in the putamen, temporo-parieto- occipital cortex, and cerebellum. With chronic potassium cyanide exposure, MR spectroscopy and SPECT may be more useful in documenting abnormalities when the standard MR scan does not reveal extensive abnormalities. Cyanide intoxication can also cause a different syndrome without parkinsonism: cerebellar dyssynergia, ataxia and accompanying malaise, weakness, visual disturbances, and muscle pains. Vertigo and unusual periods of fluctuating consciousness have also been observed. Finally, chronic cyanide intoxication caused by a long-standing ingestion of the cassava root has also been linked to tropical amblyopia and tropical ataxic neuropathy. Cassava is the tuberous root of the shrublike plant Manioc palmatea, and this plant contains a high concentration of glycoside, which is metabolically transformed into cyanide by the action of hydrolase activated by handling, heating, or bruising the tubers. Farmers and subjects in close contact with cassava have been affected most frequently. Clinically, this chronic intoxication is manifested by optic atrophy, bilateral nerve deafness, and spinal cord damage with weakness and loss of vibratory and touch sensation and diffuse polyneuropathy involving distal nerves. The lower limbs are most frequently involved and show marked weakness and wasting. In terms of signs of movement disorders, an occasional patient reveals cerebellar findings of staggering gait, poor coordination, and slurred speech. In an area of Mozambique, where an epidemic of spastic paraparesis developed in association with cassava ingestion, high urinary thiocyanate and decreased inorganic sulfate excretion were documented. These findings suggested a high cyanide exposure and have further added evidence to the hypothesis that cyanides may relate to the pathogenesis of some types of spinal ataxia and peripheral nerve lesions heretofore considered to be idiopathic or of unknown cause. In the 1970s, the anticancer drug, laetrile, was used in many areas of the world, and at its height, an estimated 20 000–50 000 people used the drug on a yearly basis. The drug induced many cases of cyanide toxicity, most notably, a mixed neuropathy–myelopathy with ataxia and dyssynergia occurring in some patients. The toxicity of laetrile related to cyanide release during the metabolism of amygdalin, a major component of the drug. Patients usually recover spontaneously from poisoning due to cyanide gas inhalation if they can be brought into open air before respiration ceases. Artificial respiration is imperative if there is interruption of breathing. For specific treatment, the National Poison Center network recommends sodium nitrite, amyl nitrite, and sodium thiosulfate, with close attention to blood pressure. See also: Parkinson’s Disease: Definition, Diagnosis, and Management.

Cylinder Test (Paw Reach Test)

Further Reading Cliff J, Lundqvist P, and Rosling H (1985) Association of high cyanide and low sulphur intake in cassava-induced spastic paraparesis. Lancet 2(8466): 1211–1213. Di Filippo M, Tambasco N, and Muzzi G (2008) Parkinsonism and cognitive impairment following chronic exposure to potassium cyanide. Movement Disorders 23: 468–469. Famuyiwa OO, Akanji AO, and Osuntokun BO (1995) Carbohydrate tolerance in patients with tropical neuropathy – A human model of chronic cyanide intoxication. African Journal of Medical Sciences 24: 151–157. Goetz CG, Kompoliti K, and Washburn K (1996) Neurotoxic agents. In: Joynt RJ and Griggs RC (eds.) Clinical Neurology, vol. 2, pp. 1–112. Philadelphia: Lippincott-Raven. Hall VA and Guest JM (1992) Sodium nitroprusside-induced cyanide intoxication and prevention with sodium thiosulfate. American Journal of Critical Care 1: 19–25.

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Holland MA and Kozlowski LM (1986) Therapy reviews: Clinical features and management of cyanide poisoning. Clinical Pharmacology 5: 737–741. Kalyanaraman UP, Kalyanaraman K, Cullinan SA, et al. (1983) Neuromyopathy of cyanide intoxication due to ‘‘laetrile’’ (amygdalin): A clinicopathologic study. Cancer 51: 2126–2133. Kanthasamy AG, Rathinavelu A, Borowitz JL, and Isom GE (1994) Interaction of cyanide with a dopamine metabolite. Neurotoxicology 15: 887–895. Rochinger J, Fellner FA, Steiglbauer K, and Trenkler J (2002) MR changes after acute cyanide intoxication. American Journal of Neuroradiology 23: 1398–1401. Rosenberg NL, Myers JA, and Martin WRW (1989) Cyanide-induced parkinsonism: Clinical, MRI and 6-fluorodopa PET studies. Neurology 39: 142–144. Rosenow F, Herholz K, Lanfermann H, and Weuthen G (1995) Neurological sequelae of cyanide intoxication. Annals of Neurology 38: 825–828. Yamamoto H (1995) A hypothesis for cyanide-induced tonic seizures with supporting evidence. Toxicology 95: 19–26.

Cylinder Test (Paw Reach Test) S B Dunnett, Cardiff University, South Wales, UK ã 2010 Elsevier Ltd. All rights reserved.

Glossary 6-OHDA – 6-Hydroxydopamine, a neurotoxin that induces selective degeneration of catecholamine neurons, frequently used following injection into the vicinity of midbrain dopamine neurons to induce an animal model of Parkinson’s disease. L-dopa – L-dihydroxyphenylalanine, the active precursor for the neurotransmitter dopamine, and the prototypical drug for treatment of Parkinson’s disease. MCAO – Middle cerebral artery occlusion, a frequently used method to induce focal stroke in the brain of experimental animals.

The cylinder test was introduced in the mid-1990s by Timothy Schallert as a simple and sensitive test of spontaneous limb use for applications in rat lesion models of Parkinson’s disease. The test turns out to be useful for assessing the sensorimotor consequences of a range of unilateral lesion models, in particular when induced by stereotaxic injection of toxins or focal ischemia. The test relies on the spontaneous tendency for rodents, when placed in a novel environment, to explore by rearing to look around. When tested in a confined space, the rats will place their forepaws against the wall to maintain stability and place their paws back on the floor to balance as they

descend. A normal rat will typically use both paws equally, with the splaying of the digits as the paw contacts the wall, but unilateral brain damage typically yields impairments in the use of the contralateral limb, with the forearm held loose or against the body and the paw more clenched.

The Cylinder Test The cylinder test (Figure 1) involves placing the animal into a transparent Perspex cylinder 20 cm in diameter and 30 cm high (sufficient to allow free rearing and turning but to avoid the animal climbing out). An angled mirror is placed behind the cylinder so that the animal’s movements can be observed at all angles. Typically, the rat is placed into the cylinder and movements video recorded for a fixed period, say 5 min, for subsequent analysis in terms of the number and duration of rears, number and duration of left and right paw contact with the wall surface, and whether the animal uses one or both paws for weight bearing when it descends from rearing. The simplest outcome measure is to express the time or number of wall contacts with the ipsilateral paw as a ratio of total time or contacts with both paws. For some purposes, such as tracking recovery of function or effects of experimental therapeutics, this simple ratio measure is the most practical. For other purposes, such as comparing