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Toxicities Associated with Oxymatrine
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The published article below reports neurological toxicities found in individuals who took oxymatrine also known as Sophora subprostrata root (SSR). In the Author discussion below are highlighted sections referring to oxymatrine & the Case reports below discuss the details of the patient's experiences.
"Movement Disorders Possibly Induced by Traditional Chinese Herbs"
European Neurology
Vol. 50, No. 3, 2003
X.P. Wanga,b, R.M. Yangb
aLaboratory of Neurodegenerative Diseases, School of Life Sciences, University of Science and Technology of China, and
bInstitute of Neurology, University Hospital, Anhui College of TCM, Hefei, PR China
Abstract
The authors describe the neurological presentation and CT/MRI findings in 4 patients exposed to overdoses of decoctions of two different Chinese herbs. Case 1, a 15-year-old boy, ingested herba serissae along with the safe-dosage Salvia miltiorrhiza for treating a left renal stone. Sophora subprostrata root (SSR) was primarily used for treating three other diseases: viral B hepatitis in case 2, a 9-year-old boy; infection of the throat and a low fever in case 3, a 11-year-old girl, and a minor facial infection in case 4, a 12-year-old boy. All patients showed complex neurological manifestations primarily including convulsions, mental changes and dystonia syndromes. Their CT and/or MRI revealed abnormal density lesions in the striatum and globus pallidus bilaterally. They excluded the possibility of Wilson's disease in each of the 4 patients and suggested that overdosage of SSR and herba serissae could cause intoxications of the central nervous system, particularly damage to the basal ganglia. Chemically, coumarin (case 1) and matrine and oxymatrine (cases 2-4) in the two medicinal herbs are suggested to be possibly responsible for the morbidity.
Author Contacts
Dr. Xiao-Ping Wang
Laboratory of Neurodegenerative Diseases, School of Life Sciences
University of Science and Technology of China
Hefei 230026 (PR China)
Tel./Fax +86 551 3607778, E-Mail wangxp@mail.hf.ah.cn
Introduction
Reports about movement disorders induced by traditional Chinese medicinal herbs are rarely seen in the current neurology literature in the English language, although there are reports of movement disorders induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and its analogs in humans [1, 2]. Severe neurological complications following intoxication with Chinese herbs are less well known than their liver and renal toxicity. Administration of natural medicinal Chinese herbs has been largely confined to Chinese ethnic groups, but now their use seems to become more popular all over the world, for example in the treatment of hepatitis [3]. In our general hospital of traditional Chinese medicine (TCM) in mainland China, medicinal herbs are a key source of alternative therapy and of all medicines consumed, medicinal herbs are only slightly less used than drugs of modern medicine. Compared with peripheral toxicity represented by neuropathy in humans [1], central nervous deficits may occasionally occur after acute or subacute exposure to a medicinal herb. The related symptoms may be convulsions, tremor, myoclonic movements, generalised dystonia, as well as blepharospasm and oromandibular dystonia, psychosis-like seizures, and unconsciousness [4]. In this report, we describe clinical manifestations and neuroimaging changes, especially with particular CT/MRI abnormalities of the basal ganglia, experienced by 4 patients as a result of oral toxicity of 'specific' decoction preparations of medicinal herbs given to them by medical amateurs.
Discussion
Movement disorders result from dysfunction of deep subcortical grey matter structures termed the basal ganglia. There is no universally accepted anatomic definition of the basal ganglia. Generally, the chief nuclei of the basal ganglia are the striatum and globus pallidus. The dopamine-, serotonin-, acetycholine- and noradrenaline-containing inputs seem to have a different and important role in striatal processing beyond the informational inputs the striatum receives from the neocortex [10]. Identification of the intoxication possibly induced by the Chinese herbs and the related symptoms need to be clarified.
The diagnostic criteria of delayed dystonia induced by intoxication were summarised as five items [11]: (1) The history of experience with the specific toxin or drug; (2) initially there are gastro-intestinal symptoms and/or of acute encephalopathy; (3) generalised dystonia or torsion spasm occurs within a period ranging from 7 to 40 days following the intoxication; in other words, dystonia is delayed; (4) once general dystonia occurs, all the neural symptoms will be stable and not progressive; (5) exclusion of infectious diseases, genetic and metabolic disorders.
All cases basically exhibit these five clinical characteristics, especially the acute onset and delayed dystonia. As for criterion 3, generalised dystonia and the other extrapyramidal symptoms, all 4 patients began to develop these signs within approximately 7, 14, 32 and 18 days, respectively, after ingestion of the medicinal herbs. The extent and degree of reversibility might depend on the severity and duration of exposure and the particular kind of toxin. Interestingly, case 3 appeared not to support criterion 4 because she had seizure-like attacks even after 6 months. For the legal issues in China, the remaining 'toxin candidate' herbs had to be originally sealed and investigated, and individually confirmed by animal tests, so poisoning induced by other materials can be excluded.
The imaging data revealed neuronal inflammation and degeneration in the early stage, and later possibly postnecrotic lesions in the basal ganglia; however, the cerebral cortex and diencephalons seemed normal, which is partly similar to the imaging of WD. As these 4 cases experienced similar clinical courses, and especially showed substantially analogous neuroimaging changes solely localised to the striatum and paleostriatum we suggest that neuronal degeneration and even neuronal necrosis in the striatum may be induced by toxins of those medicinal herbs.
WD is easily excluded in these patients based on the definite histories and copper-related biochemical tests. Leigh's disease usually occurs in infants, and causes mental retardation, movement disorders and epilepsy, which is related to increased levels of plasma lactic acid and pyruvic acid partly because of vitamin B1 deficiency. As reported by Choi [12], of 242 patients with carbon monoxide poisoning, movement disorders were diagnosed in 9.5% and the latency before the appearance varied from 2 to 26 (median 4) weeks; all patients showed encephalopathy with cognitive disorders; the common symptoms were gait disturbance, impaired mental state, urinary incontinence, and mutism. In another intoxication following the ingestion of the mycotoxin, 3-nitropropionic acid in children [11], delayed dystonia following initial gastro-intestinal symptoms and acute encephalopathy was primarily identified, and the severe intoxication was usually heralded by coma, with dystonia appearing 7-40 days after recovery from the coma; the dystonia manifested as choreoathetosis, torsion spasms, or painful paroxysmal spasms; CT showed bilateral hypodensities in the lenticular nuclei.
Individual sensitivity may influence the toxic pathogenesis; the basal ganglion itself is much more susceptible than the cerebral cortex [13]. The true reason is currently unknown. Nevertheless, the basal ganglia are especially sensitive to the lack of blood oxygen and other risks, e.g., CO [12], MPTP, nuclear icterus of the newborn, some infectious disorders [14], external manganese intoxication, internal copper poisoning in WD [7], coproducts of petroleum, and herb overdosage [15].
We would like to comment on the other clinical characteristics as follows:
(1) Why were all the patients intoxicated by the Chinese herbs and 3-nitropropionic acid so young [11]? Possibly, children are particularly sensitive to overdosage of Chinese medicinal herbs just as a newborn is susceptible to severe blood jaundice, and younger patients are more readily considered as WD, whereas the same symptoms in older patients tend to be mistaken for stroke attacks if some 'quiet' lacunar lesions and cerebrovascular risks existed.
(2) Epilepsy-like seizures or true epilepsy might originate from injuries to the basal ganglia, but strangely there were normal video scalp EEG results in this group of patients. It is believed that the specific kind of basal-ganglionic epilepsy observed in our patients was due to degeneration of basal ganglia. We have observed epilepsy in 3-5% of thousands of WD patients and suggest that if their primary extrapyramidal symptoms occurred markedly on one side, then possible epilepsy attacks would usually be triggered on the ipsilateral side.
(3) HDS-R showed case 1 to have moderate dementia. His cognitive deficits may have resulted either from potential cortex injuries, or from disorders of the basal ganglia. Cognitive insufficiency of the basal ganglion has been studied extensively; e.g., cognitive impairments induced by amygdala and putamen injuries [16], especially procedural or nonverbal implicit learning [17].
(4) In 2 cases, persisting states of 'apraxia of eyelid opening' may not be apraxia. They sometimes opened their eyelids easily if they were alone. An EMG in 1 case revealed that the oculomotor muscles of levator palpebrae and orbicularis oculi stayed almost continuously in the tonic state, while the patient tried to relax. The resting potential could not be tested accurately and EMG in the peripheral facial nerve and ophthalmic nerve was normal. Goldstein [18] defined this phenomenon of involuntary levator inhibition as apraxia. Lepore [5] found no evidence of persistent orbicularis oculi contraction or dysfunction of the oculomotor nerve, and thus considered that it was not an apraxia. It seems that involuntary levator inhibition, a kind of local dystonia, is complicated with generalised dystonia in these patients. An involuntary levator disorder may also be related to neuropsychological disturbances. We suggested that this contradictory phenomenon resembled the frozen feet phenomenon observed rarely in extrapyramidal disorders such as Parkinson's disease or WD [19].
(5) Methylprednisolone and L-dopa might improve the symptoms in early illness, because the former acts as a neuroprotective (eliminating free radicals) or anti-inflammatory agent, and the latter as a precursor of the neurotransmitter dopamine. L-dopa has long been used for awakening patients from unconsciousness [20] and inhibiting the effects of alkaloids and other toxins of medicinal herbs with acetycholine-like effects. L-dopa has been considered an effective drug for some forms of primary/secondary dystonia, and especially dopa-responsive dystonia.
SSR has been considered as an antipyretic and anti-infective agent for thousands of years; it contains various biochemical components which can be mainly classified into two groups: alkaloids and flavonoids [21]. The flavonoids are subdivided into four types: flavonones, chalcones, isoflavonones, and isoflavones [22]. SSR also contain other chemical components: (+)-sophocarpine N-oxide, (+)-sophoramine and (+)-sophoranol. Ding et al. [23] identified subprosides I, II and III. However, presently medical attention should focus on alkaloids. Alkaloids make up 0.93% of the dry weight of SSR (matrine 0.52%, oxymatrine 0.35%), so other trace chemical components, such as methylcytisine, are present in too small quantities to cause toxicity. Oxymatrine administered per os is mostly transformed into matrine in the human gut. The median lethal dose (LD50) of matrine and oxymatrine, administered intraperitoneally, is 652.0 ± 47.3 and 572.2 ± 48.8 mg/kg in the mouse, respectively [15]. A toxicological test showed that matrine increased the heart rate and blood pressure in the dog, and furthermore was antagonised by a noradrenaline receptor alpha subtype blocker: tolazoline (benzazoline). Matrine and methylcytisine have also acetycholine-like and particularly nicotinic-like excitation effects on the receptor subtype N. If the alkaloids are given in overdosage, the intoxication resembles the emergent poisoning of organic phosphate esters [4]. The affected individual develops discomfort, nausea, vomiting and dizziness, sweating, dysphagia, dysarthria, as well as other acetycholine-like symptoms: diarrhoea, muscle spasm, generalised convulsions, transient coma, acute respiratory failure and even sudden death. The pathogenesis of the delayed movement disorders or the prolonged degeneration/necrosis might be similar to those of delayed worsening of carbon monoxide poisoning after acute poisoning and a clinically silent period. The Chinese National Pharmacopoeia identifies the adult maximum dose of SSR as 9 g/ day and the adult toxic dosage as 30 g [15]. But the 3 children had received 30-40 g. In 1976, the toxic effects of SSR were investigated in rats by the Drugs Agency of Tianjing China; these studies showed that the neurodegenerative damage occurred in the striatum, forebrain and limbic system. Damage induced by SSR was also observed in 7 other published Chinese case reports [4, 9].
(4) Tang XF, Huang G, Wang JM: A case of dystonia induced by Sophora subprostrate root. Zhonghua Yi Xue Za Zhi 1999;79:896.
(9) Wang XP, Li BH, Li K, Yang RM: Toxic encephalopathy induced by traditional medicinal herbs (in Chinese). Clin J Anhui TCM 1990;12:208-209.
HS is believed to be an agent that can promote gut movements [15]. It contains volatile oils (coumarin as the main chemical component), plant sterols, alkaloids, thymohydroquinone, taraxasterol, palmitic acid, alpha-amyrin, beta-sitosterol, epifriedellinol, suberone, tannin, and flavonoids. Coumarin is very toxic in fresh HS. To our knowledge, no human poisoning by HS has been reported in the modern literature. Eupatorium urticaefolium in the USA had been reported as a poisonous plant that may induce trembling and weakness in cattle [24] induced by coumarin; coumarin is thus the principal toxic along with its derivatives [25]. Milk sickness in humans, commonly seen in Western countries [26], is probably due to coumarin or its derivatives that are contained in Eupatorium. However, the content of coumarin varies greatly according to the season and location. The ancient Chinese literature notes that 'strong cattle might tremble or stagger and even suddenly die' if they ate too many fresh HS leaves. Chinese Materia Medica states that the maximum adult dose of HS (fresh state) is 60 g/day, but case 1 had 75 g for 3 days. Radix salviae miltiorrhizae 30 g/day also in case 1 is basically safe (routine dosage: 9-30 g daily).
In contrast to Ishikawa et al. [27], who reported on the beneficial effects of another Chinese medicinal herb, kampo kami-shoyo-san, on tremor in Japanese patients with parkinsonism, our study reports opposite clinical results due to an overdose of herbs. In China, medicinal herbs can be easily collected and processed by medical amateurs without legal restrictions. However, it is emphasised that Chinese herbs should only be prescribed by fully trained practitioners of TCM, following an individualised traditional diagnosis. To test the changes in the basal ganglia and hippocampus, we performed experiments on rats intoxicated with these herbs compared with 6-OHDA which showed changes in NMDA receptors, as well as in the dopamine and the acetycholine system, especially necrosis of the basal ganglia by neurophysiological and neuropathological techniques [28].
Matrine and oxymatrine in SSR and coumarin in HS are suspected to be responsible for the intoxications. Clearly, analysing these herbs for their chemical components and testing each component to find out which one actually causes the problems is important. However, it is equally important to pay attention to these disorders, so that we can prevent such tragedies from occurring in clinical practice.
Case Reports
Case 1
Boy, 15 years old. Complaints were fits of generalised convulsions and transient unconsciousness, dysphagia, and diarrhoea for 5 days, leading to an emergency admittance on September 16, 1999. He had been diagnosed 12 days previously with a left renal stone, and managed illegally by non-professionals with a specific decoction of medicinal herbs containing fresh herba serissae (HE) 75 g along with radix salviae miltiorrhizae 30 g a day. Seven days previously, he had developed discomfort, nausea, vomiting and dizziness following the consecutive 3-day oral treatment.
Physical examination revealed marked sweating, apathy of facial expression, mild intermittent 'apraxia of eyelid opening' [5] (fig. 1), no spontaneous nystagmus; dysphagia, dysarthria, oromandibular dystonia with difficulty in closing his mouth and dislocation of upper and lower jaw closing, difficulty in sticking his tongue out; generalised dystonia in trunk and limbs and evident posture tremors in head, neck and trunk when lying on his left side. During the first 2 weeks, his muscular tone was low, but then switched to the cogwheel-like phenomenon with diminished tendon reflexes, bilateral Babinski's sign and other pathogenic reflexes. Muscle strength in all limbs appeared to be below grade III. Extensive fasciculation was seen in his face and all limbs. The family history was unremarkable: he has a healthy identical-twin brother in the army (fig. 2).
The local hospital had considered a diagnosis of Wilson's disease (WD) because of his extrapyramidal symptoms and the abnormal MRI findings (fig. 3), so he was referred to our medical institution, where further examination showed [6, 7] no Kayser-Fleischer rings on observation with the slit lamp, and negative laboratory results, e.g., serum copper 15.9 µmol/ml and caeruloplasmin 305 µg/ml, and urinary copper content 32 µg/24 h. The video EEG was within normal limits. Routine biochemistry tests, e.g. liver and kidney functions, were normal. We excluded diabetes, infectious encephalitis, and WD, so he was diagnosed with subacute basal ganglionic encephalopathy (striatum necrosis induced by a toxin). He was treated intravenously with methylprednisolone 1.0 g daily for 3 days, then an intravenous injections of L-dopa at an initial dose of 250 mg; the dose was gradually increased to 1.0 g/day; the treatment was continued with oral carbidopa-levodopa for 8 weeks. Besides acupuncture 2and rehabilitation, his painful tonic dystonia was also improved by an intramuscular injection of botulinum toxin 100 U followed by a second injection of 200 U [8]. At the time of discharge from hospital his score on the Revised Hasegawa's Dementia Scale) still revealed cognitive deficits (score <20). However, his muscle strength in all limbs had dramatically improved to grades IV-V and he could stand with the help of one person (fig. 2).
Case 2 (took oxymatrine)
Boy, 9 years old. He had suffered from chronic viral B hepatitis in 1995, and had taken a specific decoction that contained an overdosage of Sophora subprostata root (SSR), 40 g/day for 3 consecutive days, producing symptoms similar to those of case 1. He initially felt discomfort, nausea, vomiting and dizziness, and 3 h later suffered generalised convulsions and unconsciousness, followed by slight dysarthria. Two weeks later, he developed dysphagia, sweating, difficulty in extruding his tongue, serious dysarthria, generalised dystonia, heightened muscle tone with near normal muscle strength in all four limbs, hyperactive tendon reflexes, bilateral Babinski's sign (+), and fairly constant 'apraxia of eyelid opening' when people were present and during visits from doctors, which occurred particularly at the time of volitional eye-opening. The state of his eyelid opening persisted until the next natural blinking action if the lids were not closed by an investigator. When apparently unobserved, he sometimes opened his eyes voluntarily.
EMG revealed an involuntary levator disorder with the oculomotor muscles of levator palpebrae and orbicularis in almost continuous contraction, even when asked to relax his whole body. Only transitory and incomplete eyelid-opening was observed, so that the simple resting potential could not be tested accurately and was mixed with fits of interference voltage. Nevertheless evoked potentials and latency stages in the peripheral branches of the facial and ophthalmic nerves were normal. Cranial CT identified areas of bilateral striatum with a mass of hypodensity lesions across the putamen, but both CSF and video EEG investigations were normal. No Kayser-Fleischer ring was observed and laboratory investigations of serum copper, caeruloplasmin and 24-hour urinary copper content all spoke against the possibility of WD. A final diagnosis of subacute basal ganglionic encephalopathy (striatum degeneration induced by a toxin) was made. Before admission to our hospital, he had experienced non-specialist neurological treatment for 6 months. The boy was treated intravenously with dexamethasone 2 mg/kg daily for 2 weeks, then with intravenous injections of L-dopa, but there was no significant improvement of his extrapyramidal symptoms.
Case 3 (also took oxymatrine, aka SSR)
An 11-year-old girl [9]. She had been given only one dose of SSR 40 g on January 9, 1992, for a sore throat and low fever. Two hours later, she suffered from dizziness, nausea, vomiting, and half an hour later she displayed generalised convulsions, followed by unconsciousness for about 30 min. In the meantime, both CSF and EEG investigations were normal. On February 11, she had dysarthria, dysphagia, difficulty in extruding her tongue, generalised dystonia, increased muscle tone (as lead pipe), but with normal muscle strength in all limbs, hyperactive tendon reflexes and bilateral Babinski's sign (+). In early August of 1992, she had another seizure-like attack of tonic-clonic nature; however, the EEG was again normal. Cranial CT identified the area of bilateral striatum with a larger mass of low-density lesions. No corneal Kayser-Fleischer ring was seen, and all the copper-related biochemical tests excluded the possibility of WD. She was finally diagnosed as having subacute basal ganglionic encephalopathy (striatum degeneration induced by a toxin). Her extrapyramidal symptoms did not improve.
Case 4 (took oxymatrine)
Boy, 12 years old. In 1989, he had been given SSR 30 g for 7 consecutive days for treatment of a minor face infection. He also suffered from dizziness, nausea, vomiting, and half of an hour later developed generalised convulsions and unconsciousness for 15 min. Three weeks later, he had dysarthria, dysphagia, difficulty in extruding his tongue, generalised dystonia, especially in the left limbs, hyperactive tendon reflexes and bilateral Babinski's sign (+). Muscle tone was raised in all limbs; muscle strength being approximately normal. CT showed areas of bilateral striatum with a large mass of hypodensity lesions. CSF was normal and video EEG showed no epileptic waves. There were no Kayser-Fleischer rings and all the copper-related tests excluded WD. Ultimately, he was diagnosed as having subacute basal ganglionic encephalopathy (striatum degeneration induced by a toxin), which was ameliorated slightly by antisymptom therapies.
Neuroimaging Materials
In case 1, at an early stage of the intoxication, MRI (fig. 3) suggested neuropathological changes in the internal grey nuclei considered as neuronal degeneration and even neurological necrosis; MRI also showed an enhancement of the size of the striatum and the pallidum evoking oedema. The relatively sensitive MRI T2-weighted signals revealed slightly larger lesion areas than T1-weighted imagings. Because of these findings other hospitals had sent these patients to our institution. At the later stage, the main MRI neuroimaging lesions (fig. 4) were at the level of the putamen, caudate and globus pallidus (paleostriatum) with bilaterally symmetric changes, and the density of long T1 and T2-weighted signals was almost equal to that of watery CSF, which in fact resulted from the post-necrotic lesions; however, the cerebral cortex and diencephalons seemed normal. These were partially similar to the neuroimaging changes of the terminal neurological type in WD. In the other 3 cases (cases 2-4), CT showed the areas of the striatum (putamen, caudate) and globus pallidus bilaterally with a large mass of symmetric and low-density lesions; the density of these lesions was not as low as that of CSF, which might suggest degeneration of the basal ganglia. Both the abnormal densities of CT and MRI T1- and T2-weighted signals in the 4 cases tend to resemble those of infarcted lesions in ischemic cerebrovascular diseases, but the latter are basically not bilaterally symmetric, and, in particular, often invade the internal capsule.
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