German Journal of Psychiatry
Moderate hyperhomocysteinemia and neuropsychiatric symptoms in manganese-induced parkinsonism
Stefan Bleich, Detlef Degner, Borwin Bandelow, Antje Riegel1, Juan M. Maler, Eckart Rüther, and Johannes Kornhuber
Department of Psychiatry
1Department of Neuroradiology
Georg-August University of Göttingen, Germany
Corresponding author: Stefan Bleich, M.D, Department of Psychiatry, Georg-August University of Göttingen, von-Siebold-Str. 5, D-37075 Göttingen, Germany; e-mail firstname.lastname@example.org
Manganese intoxication is a well-known cause of parkinsonism and dementia. Here we present the case of an 80-year-old patient with proven manganese poisoning. We observed no long-term progression of the manganese-induced parkinsonian syndrome. The blood manganese concentration is now reduced to below the normal range (4.8mg/l), but the manganese concentration in scalp hair (2.79mg/g) has kept on increasing. Strikingly, even though we found normal cobalamin and even elevated serum folate levels, we observed a moderate hyperhomocysteinemia in two independent samples. We did not find any common known risk factors for this moderate hyperhomocysteinemia The possible role of hyperhomocysteinemia in manganese-induced parkinsonism is discussed (German J Psychiatry 2000;3:14-20)
Key words: manganese, homocysteine, parkinsonism
Received: Dec. 18, 1999
Published: Jan. 25, 2000
Various metals (i.e. lead, copper, manganese) have been implicated in neuropsychiatric diseases (Youdim et al., 1991). Chronic manganism, while uncommon, is by no means rare. Manganese is used in metal alloys, in the manufacture of chlorine gas, dry battery cells, paints, varnish, enamel, and linoleum, in the process of coloring glass and soaps, and as an antiknock agent in lead-free gasoline. Manganese intoxication is a well-known cause of many neurologic and psychiatric disorders including parkinsonism and dementia (Huang et al., 1989). The central nervous system is frequently involved, usually in the area of the extrapyramidal motor system. A morphometric study revealed pathological degeneration of ganglion cells in the putamen, globus pallidus and caudate nucleus due to manganese poisoning (Moeschlin, 1980). The presenting signs of chronic manganism include disorientation, impairment of memory and judgment, acute anxiety, emotional lability, compulsive acts, hallucinations, illusions, and delusions (Huang et al., 1989). In addition, magnetic resonance imaging (MRI) has been suggested to be useful in the diagnosis of manganese intoxication due to the determination of a high-intensity signal on T1-weighted MRI in the basal ganglia (Arjona et al., 1997). MRI findings suggestive of hyperhomocysteinemia are signs of cerebrovascular occlusive disease and/ or demyelination (van den Berg et al., 1995) and pathologic changes in manganese-induced parkinsonism have been shown to be gliosis and cell loss in medial globus pallidus rather than substantia nigra. This communication describes a moderate hyperhomocysteinemia in a patient with chronic manganese intoxication.
A 66-year-old male patient with proven manganese poisoning was treated in our hospital, the complete case was published in 1986 (Holzgraefe et al., 1986): Briefly, this patient ingested 125 ml of an 8% solution of potassium permanganate (10g) within 4 weeks. The patient was repeatedly poisoned by this solution over a period of four weeks due to a mistake made in the preparation of a prescription (an 8% solution of potassium permanganate was prepared instead of an 8% solution of potassium iodate). As early as 2 weeks after the beginning of poisoning, psychological and neurological alterations such as impairment of vision, fasciculations, hemihypesthesia, impaired concentration, severe fatigue, hypersomnia, pain and muscle cramps, sweating, and increased libido were noticed. Nine months after poisoning, the first signs of progressive Parkinson's disease became evident. Beside a resting tremor, other signs of Parkinson's syndrome, such as rigor and a shortening of gait were noticed. 14 years after the intoxication, the now 80-year-old patient is still alive. We examined the patient in our hospital again. Clinical, neurological and psychiatric examination was performed in the same manner as described before (Holzgraefe et al., 1986, Bleich et al., 1999). The clinical summaries of the patient´s symptoms from 1984 to 1998 were compared. He was alert, oriented, and coherent but slow in mentation. His speech was slightly dysarthric and a shortening of the patient's gait was noticed. The gastrocnemius tendon reflex was reduced bilaterally, hemihypesthesia was reported in both hands and there was a symmetrically diminished perception of vibration of the lower extremities. Coordination was impaired. He showed no rigor, but a low-grade resting tremor and ubiquitous muscle fasciculations of variable intensity in the upper extremities. He displayed no evidence of hallucinations or delusions, he still complained of disturbances of concentration. Most symptoms improved, including disturbances such as rigor, muscle pain or cramps, hypersomnia, increased libido, sweating, fatigue, concentration, and anxiety.
Fasting blood samples were collected in ethylenediaminetetraacetic (EDTA) acid-containing tubes and were promptly centrifuged following collection. Plasma was stored at 80°C. Vitamin B12 and serum-folate concentrations were measured by chemiluminescence using Chiron kits (Chiron Diagnostics Corporation/ Fernwald, Germany) on a Chiron ACS: 180 automated analyser. Vitamin B6 was determined by HPLC using an Immunodiagnostik kit (Immunodiagnostik/ Bensheim, Germany). Homocysteine was determined by HPLC (Ling et al., 1991) using a Bio-Rad kit (Bio-Rad/ Munich, Germany). The patient received no pharmaceutical folate supplementation. Cranial MRI and genotyping for the thermolabile MTHFR variant revealed no abnormalities.
Results of blood cell counts, liver-function tests, serum protein electrophoresis, ceruloplasmin, a2-macroglobulin, transferrin, blood lipids including cholesterol, glucose, creatinine, uric acid, iron, vitamins (B6, B12) and other routine analyses were normal. Strikingly, even though we found normal cobalamin of 519 ng/l (normal range: 170-850ng/l) and even elevated serum folate levels of 27.1 mg/l (4-17 mg/l), we observed a moderate hyperhomocysteinemia of 28.2 mmol/l (5-15 mmol/l). Seven days later in a control measurement we could confirm this result (27.6mmol/l). Using fasting blood samples we excluded that homocysteine still increases after a methionine load. During the acute stage, high levels of manganese concentration were found in blood (150 mg/l; reference level 7.1-10.5 mg/l) and scalp hair (1.6 mg/g; reference level 0.07-1.00 mg/g). The blood manganese concentration is now reduced to below the normal range (4.8mg/l), but the manganese concentration in scalp hair (2.79mg/g) has kept on increasing.
In summary, most extrapyramidal syndromes resembling Parkinson`s disease are unchanged; we did not notice a deterioration of these symptoms. Thus, we observed no long-term progression of the parkinsonian syndrome as described by others (Huang et al., 1998). Furthermore, we did not find a reduced manganese concentration in scalp hair in comparison to former studies (Huang et al., 1998).
Moderate hyperhomocysteinemia has been related to genetic or nongenetic risk factors (i.e. cardiovascular diseases). However, referring to the literature, we have no clear explanation for our observation, since we did not find any common known risk factors for moderate hyperhomocysteinemia as described by others (Refsum et al., 1998; Kang and Wong, 1996): risk factors such as nutritional status, medication (i.e. methotrexate), endocrinological conditions, other diseases (i.e. thromboembolic, cardiovascular diseases), and lifestyle habits such as smoking or alcohol intake (Bleich and Degner, 1999).
The underlying mechanisms by which manganese develops its toxicity are unknown. Hypotheses concerning its toxicity emphasize a disturbed neurotransmitter function in specific brain regions (Huang et al., 1989). The possible clinical significance of S-adenosylmethionine (SAM) in neurological disorders due to disturbed transmethylation reactions has been discussed recently (Bottiglieri et al., 1994). The demethylated product from all methyltransferase reactions is S-adenosylhomocysteine (SAH), which is rapidly metabolised to homocysteine (HCY). There is experimental evidence that homocysteine in the presence of copper or iron ions destroys or alters biomolecules such as dihydroxyphenylalanine (DOPA), which might result in dopamine deficiency (Schlüssel et al., 1995). The mechanism by which homocysteine exerts ist toxic effects remains unclear. H2O2 is a known product of the autooxidation of thiol-containing amino acids, which is possibly involved in the mechanism of homocysteine-induced toxicity due to the generation of hydroxyl radicals in the presence of metal ions (Schlüssel et al., 1995). It has also been suggested that manganese-induced oxidative stress may stimulate dopamine autooxidation within the dopaminergic neuron (Desole et al., 1997). Thus, it is possible that HCY induces oxidative stress, which is then potentiated by manganese ions. Interestingly, it has been assumed that hyperhomocysteinemia is a significant feature in Parkinson`s disease (Kuhn et al., 1998). It has been shown that homocysteine itself acts as an agonist at the glutamate binding site of the NMDA receptor (Lipton et al., 1997) and leads to an imbalance in excitatory: inhibitory neurotransmission in the hippocampus caused by alterations in extracellular levels of neuroexcitatory (e.g. aspartate) and neuroinhibitory (e.g. GABA) transmitters, which could be an explanation of the symptoms which are seen in parkinsonism (Bleich et al., 1999). However, it has to be taken into account that ageing could also be an explanation for the patient's symptoms, although it is controversial that most of the neurological and psychiatric symptoms have improved.
In conclusion, moderate hyperhomocysteinemia has been found in a patient with mild parkinsonism due to a proven chronic manganese intoxication and might possibly reflect a pathogenetic role in manganese-induced parkinsonism. Nevertheless, the possible involvement of homocysteine in manganese-induced parkinsonism needs to be elucidated in further investigations.
Arjona A, Mata M, Bonet M. Diagnosis of chronic manganese intoxication by magnetic resonance imaging. N Engl J Med 1997; 336: 964-965
Bleich S, Degner D. Whole blood folate, homocysteine in serum, and risk of first acute myocardial infarction. Atherosclerosis 1999 (in press)
Bleich S, Degner D, Kornhuber J. Repeated ethanol withdrawal delays development of focal seizures in hippocampal kindling. Alcohol Clin Exp Res 1999 (in press)
Bleich S, Degner D, Sprung R, Riegel A, Poser W, Rüther E. Chronic manganism: fourteen years of follow up. J Neuropsychiatry Clin Neurosci 1999; 11: 117
Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademethionine (S- Adenosylmethionine) in neurological disorders. Drugs 1994; 48: 137-152
Desole MS, Esposito G, Migheli R, Sircana S, Delogu MR, Fresu L, Miele M, de Natale G, Miele E. Glutathione deficiency potentiates manganese toxicity in rat striatum and brainstem and in PC12 cells. Pharmacol Res 1997; 36: 285-292
Holzgraefe M, Poser W, Kijewski H, Beuche W. Chronic enteral poisoning by potassium permanganate: A case report. Clin Toxicol 1986; 24: 235-244
Huang CC, Chu NS, Lu CS, Chen RS, Calne DB. Long-term progression in chronic manganism. Ten years of follow-up. Neurology 1998; 50: 698-700
Huang CC, Chu NS, Lu CS, Wang JD, Tsai JL, Tzeng JL, Wolters EC, Calne DB. Chronic manganese intoxication. Arch Neurol 1989; 46: 1104-1106
Kang S-S, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia. Atherosclerosis 1996; 119: 135-138
Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Przuntek H, Kretschmer A, Büttner Th, Woitalla D, Müller Th. Elevated plasma levels of homocysteine in Parkinson`s disease. Eur Neurology 1998; 40: 225-227
Ling BL, Dewaele C, Baeyens WRG. Micro liquid chromatography with fluorescence detection of thiols and disulphides. J Chromatography 1991; 553, 433-439.
Moeschlin S. Klinik und Therapie der Vergiftungen. Stuttgart: Thieme-Verlag 1980
Refsum H, Ueland PM, Nygċrd O, Vollset SE. Homocysteine and cardiovascular disease. Ann Rev Med 1998; 49: 31-62
Lipton SA, Kim WK, Choi YB, Kumar S, Dèmilia DM, Rayudu PV, Arnelle DR, Stamler JS. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proceedings of the National Academy of Science USA 1997; 94, 5923-5928.
Schlüssel E, Preibisch G, Pütter S, Elstner EF. Homocysteine-induced oxidative damage: Mechanisms and possible roles in neurodegenerative and atherogenic processes. Z Naturforsch 1995; 50c: 699-707
van den Berg M, van der Knaap MS, Boers GHJ, Stehouwer CDA, Rauwerda JA, Valk J. Hyperhomocysteinaemia; with reference to its neuroradiological aspects. Neuroradiology 1995; 37: 403-411
Youdim MB, Ben-Shachar D, Riederer P. Iron in brain function and dysfunction with emphasis on Parkinson`s disease. Eur Neurology 1991; 31: 34-40