Download Manganic encephalopathy due to "ephedrone" abuse

MANGANIC ENCEPHALOPATHY DUE TO “EPHEDRONE” ABUSE
1337
gawa disease usually manifests in infancy or childhood
with dystonic limb movements, and patients respond
well to levodopa treatment. An incomplete response to
levodopa has also been described.9 In contrast to the
classical disease presentation, dystonia resolved only incompletely with both levodopa and ropinirol. In the
adult-onset variant, symptoms often begin with arm dystonia or Parkinsonism.1,2,6 In contrast, symptoms first
occurred in one leg in our patient. Truncal dystonia or
camptocormia have not been reported previously for
Segawa disease.
In conclusion, the clinical presentation of Segawa
disease appears to be very heterogeneous. In patients
who respond well to levodopa, Segawa disease should be
considered even if dystonia manifests atypically.
9. Leenders KL, Antonini A, Meinck HM, Weindl A. Striatal dopamine D2 receptors in dopa-responsive dystonia and Parkinson’s
disease In: Segawa M, Nomura Y, editors. Age-related dopaminedependent disorders: International symposium on age-related
monoamine-dependent disorders and their modulation by gene and
gend (Monographs in clinical neuroscience, Vol. 15). Basel:
Karger; 1995. pp 95–100.
10. Robinson R, McCarthy GT, Bandmann O, Dobbie M, Surtees R,
Wood NW. GTP cyclohydrolase deficiency; intrafamilial variation
in clinical phenotype, including levodopa responsiveness. J Neurol
Neurosurg Psychiatry 1999;6:86-89.
LEGENDS TO THE VIDEO
Yanush Sanotsky, MD,1*
Roman Lesyk, PharmD, PhD,2
Lyudmyla Fedoryshyn, MD, PhD,1
Iryna Komnatska, MD,3
Yuriy Matviyenko, MD, PhD,4 and Stanley Fahn, MD5
Segment 1. The video shows the patient walking at different
speeds before and after receiving 200 mg levodopa.
Segment 2. The first sequence was taken after a 30-min
walk without levodopa. Notice the clumsy movement of the left
leg and the transient action-induced bending of the trunk forward and to the left. Depending on the walking speed, inward
rotation of the left leg and supination of the left foot develop.
Segment 3. The following sequences show the patient after
receiving 200 mg levodopa. Shortly after the start (second
sequence), minor residual symptoms are present with a clumsy
left leg and a slight bending of the trunk. After a 30-min walk
(third sequence), dystonic symptoms increase again.
Acknowledgments: We thank D. Steinberger, MD, of Bioscientia Ingelheim, Germany, for molecular genetic analysis
and helpful discussions.
REFERENCES
1. Segawa M, Nomura Y, Nishiyama N. Autosomal dominant
triphosphate cyclohydrolase I deficiency (Segawa disease). Ann
Neurol 2003;54 (Suppl. 6):32-45.
2. Steinberger D, Korinthenberg R, Topka H, Berghäuser M, Wedde
R, Müller U. Dopa-responsive dystonia: mutation analysis of
GCH1 and analysis of therapeutic doses of L-dopa. Neurology
2000;55:1735-1737.
3. Müller U, Steinberger D, Topka H. Mutations of GCH1 in doparesponsive dystonia. J Neural Transm 2002;109:321-328.
4. Nitschke M, Steinberger D, Heberlein I, Otto V, Müller U, Vieregge P. Dopa-responsive dystonia with Turner’s syndrome: clinical, genetic, and neuropsychological studies in a family with a new
mutation in the GTP-cyclohydrolase I gene. J Neurol Neurosurg
Psychiatry 1998;64:806-808.
5. Hwu WL, Wang PJ, Hsiao KJ, Wang TR, Chiou YW, Lee YM.
Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation. Hum Genet 1999;105:226-230.
6. Hagenah J, Saunders-Pullman R, Hedrich K, et al. High mutation
rate in dopa-responsive dystonia: detection with comprehensive
GCHI screening. Neurology 2005;64:908-911.
7. Bandmann O, Wood NW. Dopa-responsive dystonia—the story so
far. Neuropediatrics 2002;33:1-5.
8. Bandmann O, Valente EM, Holmans P, et al. Dopa-responsive
Dystonia: a clinical and molecular genetic study. Ann Neurol
1998;44:649-656.
Manganic Encephalopathy Due to
“Ephedrone” Abuse
1
Department of Neurology, Lviv Regional Clinical Hospital,
Lviv, Ukraine 2Department of Pharmaceutical, Organic and
Bioorganic Chemistry, Danylo Halytsky Lviv National
Medical University, Lviv, Ukraine 3Department of MRI,
Central Hospital of the Lviv Regional Railway, Lviv, Ukraine
4
Department of Neurology, Danylo Halytsky Lviv National
Medical University, Lviv, Ukraine 5Department of
Neurology, Columbia University Medical Center,
New York, New York, USA
Abstract: We describe the clinical and neuroimaging features
of 6 drug-abuse patients with self-inflicted manganese poisoning. The patients injected a home-brewed mixture called
“ephedrone” (slang term) that contained manganese to produce an amphetamine-like euphoria. The desired chemical
product, phenylpropanoneamine (also called methcathinone),
was synthesized from a common-cold–remedy compound using permanganate as the catalyst. Manganese was a by-product in the ephedrone mixture. After months of self-injections,
a clinical picture emerged, consisting of apathy, bradykinesia,
gait disorder with postural instability, and spastic-hypokinetic
dysarthria. There was no response to levodopa. The MRI
revealed symmetric hyperintense T1-weighted signals in the
basal ganglia, typical of manganese accumulation. © 2007
Movement Disorder Society
Key words: manganese poisoning; manganic encephalopathy; ephedronic encephalopathy; parkinsonism; drug-addiction.
*Correspondence to: Dr. Yanush Sanotsky, Department of Neurology, Lviv Regional Clinical Hospital, Nekrasova St. 6/8, Lviv 79010,
Ukraine. E-mail: [email protected]
Received 13 November 2006; Revised 13 November 2006; Accepted
19 November 2006
Published online 12 June 2007 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.21378
Movement Disorders, Vol. 22, No. 9, 2007
1338
Y. SANOTSKY ET AL.
Manganese is an essential element for biologic function, but excessive exposure can be toxic, particularly to
the central nervous system. The most common manifestation of manganese neurotoxicity is a parkinsonian syndrome with features of dystonia. Only 20 years after
James Parkinson’s essay1 appeared, Couper2 described a
syndrome similar to Parkinson’s disease in 5 patients
who worked in a manganese ore-crushing plant. During
the past 80 years there have been a number of similar
reports on manganism,3-7 some with dystonia as the
predominant movement disorder.8 Because manganese is
usually absorbed into the human body by oral and respiratory routes in the form of dust, the majority of cases of
manganism have been reported in underground miners,
alloy plant workers, and other individuals exposed occupationally. Other sources of manganese intoxication are
now recognized, including total parenteral nutrition in
hospitalized patients9,10 and exposure to manganese-containing pesticides in agricultural workers.11 It was also
suggested that parkinsonism in patients suffering from
chronic liver disease is related to the accumulation of
manganese in the basal ganglia due to impaired hepatic
manganese metabolism.12
Patients with a new cause of manganese poisoning—
drug-abuse— have been reported in the Russian13,14 and
Ukrainian15 literature, and the disorder was called “ephedronic” encephalopathy. The clinical picture consisted of
spastic-hypokinetic dysarthria, postural instability with
falling, “cock-gait,” parkinsonian signs (hypokinesia, hypomimia, cogwheel rigidity), bradyphrenia, hypersomnia, and myoclonus. The T1-weighted MRI demonstrated an increased signal in the globus pallidus and
substantia nigra. The patients did not respond to levodopa. The abused material is home-made and injected
intravenously to obtain the desired effect of an amphetamine-like “high” of euphoria, and often sexual
arousal.
The starting materials for the preparation of the injected mixture are readily available commercial coldremedy compounds containing phenylpropanolamine.
Acetic acid and KMnO4 (potassium permanganate) are
added to create an oxidation reaction (see Fig. 1), with
the main product being phenylpropanoneamine, also
called methcathinone.16 During the reaction, as a side
product, Mn2⫹ ions are formed, the probable cause of the
akinetic-rigid encephalopathy. The chemical mixture is
not purified before it is self-injected. The colloquial slang
term for the mixture is “ephedrone,” hence the original
reports of the syndrome being called “ephedronic” encephalopathy.13,14 Other slang terms for the mixture are
“jaff” and “mul’ka.”
Movement Disorders, Vol. 22, No. 9, 2007
FIG. 1. The chemical reactions in which phenylpropanolamine reacts
with permanganate and acetic acid to yield phenylpropanoneamine and
divalent manganese. The reactions were analyzed and determined by R.
Lesyk, PhD, Department of Pharmaceutical, Organic and Bioorganic
Chemistry, Danylo Halytsky Lviv National Medical University, Lviv,
Ukraine (personal communication).
CASE REPORTS
In the Department of Neurology of Lviv Regional
Clinical Hospital (Lviv, Ukraine) we evaluated 6 patients
who presented with a hypokinetic syndrome after having
injected themselves over a period of time ranging from 2
months to 2 years with the above-mentioned chemically
prepared ephedronic mixture. All patients underwent
general clinical investigations, including complete blood
count, ESR, electrolytes, renal and hepatic function tests,
VDRL test, ECG and abdominal sonography. All of
these tests were normal, and no signs of extraneural
disorder were detected.
Patient 1
In 2003 this 38-year-old man began to prepare and use
ephedrone with a frequency of 1 to 2 times/day because
he had a social-situational depression. In 2004 he began
having speech and gait disturbances, frequent falling,
increased appetite and apathy. After symptoms of slowness developed, he ceased using the drug without signs
of withdrawal. He sought medical attention and was seen
by us. Examination revealed hypothymia, with lack of
initiative, but also inappropriate lack of worry about his
ailment. Memory and intellect were preserved, but he did
not ask spontaneous questions and showed no interested
in his laboratory results or treatment. He did read during
his stay in the hospital. We observed low verbal activity,
diminished attention, and simplified reasoning. He described impotence. There was facial seborrhea.
Neurological examination revealed hypomimia,
speech characterized as a spastic-hypokinetic dysarthria,
hypophonia, preserved swallowing, moderate hypokinesia, and symmetric rigidity of the arms, legs and trunk.
There was no arm swing, but his steps were normal when
he walked with support. He was unable to walk independently because of marked postural instability with retro-
MANGANIC ENCEPHALOPATHY DUE TO “EPHEDRONE” ABUSE
pulsion and falling. There was slight dystonic rotation of
the feet during walking.
He was treated with amantadine, intravenous infusions
of calcium ETDA, and intravenous injections of Cerebrolysin. (Cerebrolysin is produced by enzymatic breakdown of purified brain proteins and consists of lowmolecular-weight peptides and amino acids.17) After 3
months, there was an increase in his emotional affect and
his motor activity, and he was able to walk with a cane.
A trial of levodopa was without effect and was stopped
(see Results).
Patient 2
This 23-year-old man had been injecting ephedrone
daily for half a year in 2000. We observed and treated
him over the next 3 years. Examination revealed marked
psychomotor depression with periodic explosions. He
required verbal stimulation to become active. He talked
little and had diminished attention, simplified reasoning,
and bradyphrenia. Autonomic features included impotence and seborrhea.
Neurological examination revealed facial hypomimia, soft voice with monotonous fading speech,
spastic-hypokinetic dysarthria, dysphagia, dystonic
smile, hypokinesia, rigidity, and marked gait disturbances— cock-gait, twisting feet, no arm swing, postural instability with frequent falling, retropulsion, and
lateral falling. He was unable to walk independently
without falling.
After treatment with calcium EDTA, amantadine,
and Cerebrolysin, the general status of the patient
improved. There was increased psychomotor activity,
and he began to make contact with the external environment and to talk more readily. He was able to walk
independently without support. However, retropulsion, postural instability, and dystonia of the feet were
unchanged.
1339
micrographia. On walking, there was moderate postural
instability with retropulsion and left-sided falling.
She was treated with calcium EDTA, amantadine, and
Cerebrolysin without improvement.
Patient 4
In 2003 to 2004 this 28-year-old man used ephedrone
1 to 2 times/month. He stopped it when he developed
slowness of movement, and there were no symptoms of
dependence or withdrawal effect.
Examination revealed normal emotional reactions to
verbal contact and responses to questions, but there was
low spontaneous verbal activity, inadequate self-assessment, and euphoria. The patient complained of speech
disturbances (“sticking”), with inability to say the letters
“k” and “r.” Autonomic features included impotence and
seborrhea.
Neurological examination revealed dysarthria, slow
speech, preserved swallowing, and dystonic smile. Walking was mostly intact, but sometimes he retropulsed.
There was postural instability.
He was treated with calcium EDTA, amantadine, and
Cerebrolysin, without improvement.
Patient 3
Patient 5
This 28-year-old man began injecting ephedrone once
daily for half a year in 2003. In February 2004 he
suddenly developed hyperthermia and sought medical
attention. Examination revealed no initiation of spontaneous speech. He showed no interest to his state and
responded only briefly to questions. He did not connect
with people around him, and remained uninterested in his
treatment.
Neurological examination revealed hypomimia, dystonic smile, hardly understandable, fading, and tremulous speech, elements of dysphagia, marked postural
instability, disturbed gait, and falling backwards.
He was treated with calcium EDTA, amantadine, and
Cerebrolysin, without improvement.
This 29-year-old woman had been using 2 to 3 g of
ephedrone every other day for 2 months in 2003. She
stopped the injections after the appearance of slowness
of movement. A withdrawal reaction did not occur. She
experienced total loss of the interest in her job, family,
and external environment. Examination revealed the patient to be highly emotional during conversation and with
impaired memory. She failed to understand the serious
nature of her problem.
Neurological examination revealed moderate hypomimia, spastic-hypokinetic dysarthria, dysphagia, hyperorality, slowed movements, cogwheel rigidity, and
Patient 6
This 45-year-old man had been injecting ephedrone
for 5 months in 2003 during imprisonment. Suddenly he
developed joint aches, gait disturbances, speech disturbance, depression, and suicidal ideation.
Examination revealed him to be emotionally active
and responsive to questions, but with low spontaneous
verbal activity. His memory and intellect was preserved.
Neurological examination revealed spastic-hypokinetic dysarthria, postural instability, emotional lability,
and bradyphrenia.
Movement Disorders, Vol. 22, No. 9, 2007
1340
Y. SANOTSKY ET AL.
TABLE 1. Distribution of the symptoms among the 6
investigated patients at the time of admission to hospital
Neurologic sign
No. of patients
Dysarthria
Gait disturbances
Hypokinesia
Postural instability
Autonomic signs
Hypersalivation
Impotence
Seborrhea
Cognitive dysfunctions
Emotional lability, apathy, lack of spontaneity
6
4
5
6
1
5
6
6
6
He was treated with calcium EDTA, amantadine, and
Cerebrolysin. His speech slightly improved (during reading aloud, but not in spontaneous conversation), and
there was improved postural stability, although there was
still relatively frequent falling.
RESULTS
Analysis of our 6 cases demonstrated no relation between clinical symptoms and duration of drug usage.
Frequency of injections was 1 time/week (2 patients), 3
times/week (2 patients), and 7 times/week (2 patients). In
all cases the source of phenylpropanolamine to produce
ephedrone was Coldact® (Ranbaxy Laboratories, India).
A single injection of the ephedrone mixture was ⬃10 ml.
Occurrence of symptoms and their severity did not depend on the age of the patients, but all were young to
middle-age adults. All of them had practically identical
signs. Distribution of these signs at the time of admission
is shown in Table 1.
The MRIs of the brain showed a striking bilaterally
symmetric increased signal in selected regions on T1weighted scans. These regions are the lentiform nucleus,
substantia nigra, and the dentate nucleus in the cerebellum, as seen in Patient 4 (Fig. 2a– d). Similar increased
signals have been reported in other cases of manganese
intoxication.12,18 Patient 4 underwent MRI within 1
month after the last injection of ephedrone. In contrast,
Patient 2, who had an almost identical clinical picture,
underwent MRI 2.5 years after the last injection of ephedrone (Fig. 3a– d). The marked difference in the scans,
with the latter patient showing much less increased T1
signal, suggests that there could be elimination of Mn2⫹
from the brain while residual neurologic impairment
remains.
The semiquantitative intensities of the signal amplification on the T1-weighted scans in the different brain
regions in all 6 patients are shown in Table 2. The most
consistent regions with the greatest signal intensity are
the globus pallidus and substantia nigra.
Movement Disorders, Vol. 22, No. 9, 2007
FIG. 2. T1-weighted MRIs in Patient 4. Increased signals are seen in
the substantia nigra (2a,d), dentate nucleus (2a), and lentiform nucleus
(2b– d).
Treatment was empirical, but EDTA is a standard
treatment for heavy metal poisonings. Mild to moderate
improvement was observed in 4 patients, while no improvement was seen in the other two. Whether the improvement seen was due to any of the agents or just
cessation of the self-administered ephedrone mixture
cannot be stated. The semiquantitative degree of clinical
FIG. 3. T1-weighted MRIs in Patient 2. The increased signals seen in
substantia nigra (3c), dentate nucleus (3a), and lentiform nucleus
(3a– d) are much less than those seen in Patient 4 (Fig. 2a– d).
MANGANIC ENCEPHALOPATHY DUE TO “EPHEDRONE” ABUSE
TABLE 2. Semiquantitative analysis of the intensity of
signal amplification on T1-weighted MRI scans in different
brain regions
Patient no.
Globus
pallidus
Putamen
Substantia
nigra
Dentate
nucleus
1
2
3
4
5
6
⫹⫹
⫹⫹⫹
⫹⫹⫹⫹⫹
⫹⫹
⫹
⫹⫹⫹⫹⫹
⫺
⫺
⫹⫹⫹⫹
⫹⫹
⫺
⫹⫹⫹⫹
⫺
⫹⫹⫹⫹⫹
⫹⫹⫹⫹⫹
⫺
⫺
⫹⫹⫹⫹⫹
⫹
⫹⫹
⫹⫹
⫺
⫺
⫹⫹
improvement with regard to particular signs and symptoms is presented in Table 3. Hypokinesia improved in 3
patients, gait in 3, speech in 2, while none had an
improvement in postural instability.
Because drug addicts who injected themselves with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
developed parkinsonism which responded to low doses
of levodopa,19 we evaluated the effect of levodopa in our
patients. All 6 patients were given carbidopa/levodopa
(25/100 mg) 3 times daily for 10 days; there was no
effect. Although this low dose was given as a test during
hospitalization, we initiated chronic levodopa therapy
after the patients were discharged from the hospital. The
patients continue to receive carbidopa/levodopa (37.5/
150 mg) 3 times per day.
DISCUSSION
Although reports on the neuropathology of chronic
manganese poisoning are rare, Canavan and colleagues.4
observed shrinkage, neuronal degeneration, and gliosis
of the basal ganglia in 1 postmortem case. Yamada and
colleagues20 showed that the predominant degeneration
involved the medial globus pallidus in another case. In
experimental primates, manganese poisoning caused degeneration of the basal ganglia, particularly in the globus
pallidus and substantia nigra reticulata.21,22
Because manganese is paramagnetic, signal changes
may be demonstrated during MRI if the concentrations
are high.18,23 In monkeys intoxicated with manganese,
neuroimaging alterations were seen in the pallidum, striatum, substantia nigra, and pituitary.24 In humans with
manganism, the fluorodopa PET scan was normal,25
compatible with lack of involvement of dopaminergic
nigrostriatal neurons and dopamine deficiency. This
would explain lack of response to levodopa, and supports
the concept that postdopaminergic lesions, such as the
pallidum, are responsible for the parkinsonian syndrome
seen in manganic encephalopathy.
Besides manganism, increased signal on T1-weighted
MRI-scans can be caused by accumulation of fat, mela-
1341
nin, calcifications, hemorrhages, and paramagnetic metals, such as iron, copper, and manganese. It is also
observed in states of decreased blood oxygen content,
nonketotic hyperglycemia, neurofibromatosis, and hypoperfusion. Taking into account that all 6 patients injected
themselves with solutions containing manganese, and
manganese accumulates in the same regions in which
hyperintense signals are seen, it is reasonable to suggest
that clinical encephalopathy of these patients is associated with accumulation of manganese ions in the brain,
hence a manganic encephalopathy.
Although the clinical reports3-5 vary somewhat, it is
generally considered that manganic encephalopathy
starts gradually with nonspecific symptoms, often of a
psychiatric nature (“manganese madness”). After a few
months, parkinsonism and often dystonia appear and
persist. A characteristic finding is the so-called cockgait,26 in which patients strut on their toes, with elbows
flexed and the spine erect; this is quite unlike the usual
clinical picture of Parkinson’s disease or dystonia. It is
notable that patients can develop the motor deficits of
manganism without having experienced any phase of
manganese madness.27 Another distinguishing feature is
a propensity to walk backward.28 Tremor tends to be
absent.
Treatment of manganism is far from clear. Rafael29
reported that treatment with EDTA, caramiphen HCl,
mephenesin, and vitamin C in a 32-year-old manganese-poisoned miner led to full resolution of motor
symptoms and mental disturbances. Mena and colleagues30 and Rosenstock and colleagues31 reported
marked improvement of dystonia and parkinsonism
with levodopa after short-term observations, but
Huang et al.28 found that any initial improvement is
eventually lost. There is only one double-blinded
study with levodopa,32 and this failed to show improvement. Isolated reports of other positive therapeutic responses include the use of sodium para-aminosalicylic acid.32 Attempts to chelate manganese have
not helped patients.33 Claims for the efficacy of other
TABLE 3. Semiquantitative degree of clinical improvement
with regard to particular signs and symptoms
Patient no.
Dysarthria
Gait disturbances
Postural instability
Hypokinesia
Autonomic features
Depression
1
2
3
4
5
6
⫹⫹
⫹
⫺
⫹
⫹/⫺
⫹⫹
⫹
⫹
⫺
⫺
⫹
⫹
⫺
⫹
⫺
⫹
⫺
⫹
⫺
⫹/⫺
⫺
⫹
⫹
⫹
⫺
⫺
⫹/⫺
⫺
⫺
⫺
⫺
⫹/⫺
⫺
⫺
⫺
⫺
Movement Disorders, Vol. 22, No. 9, 2007
1342
Y. SANOTSKY ET AL.
TABLE 4. Clinical differences between intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
and ephedronic encephalopathy
MPTP-intoxication
Ephedronic encephalopathy
Tenderness during injection
First signs of substance action
Intellectual deficit
Yes
Euphoria, hallucinations
Absent
Onset of symptoms
Generalized muscular twitching, dystonic hyperkinesias
Evolution of symptoms
Generalized muscular twitching and dystonic
hyperkinesias with subsequent development of
parkinsonism
Very good
Response to levodopa
medications remain equally unproven. The primary
therapy remains removing the patient from manganese
exposure and preventing further exposure.
The 21 cases of so-called ephedronic encephalopathy
reported by Levin et al.13,14 and our own 6 cases add
another cause of manganic encephalopathy. That the
encephalopathy from self-injections of the ephedrone
mixture is due to the manganese in the mixture is supported by the typical clinical picture of manganism and
the typical symmetric MRI appearance of increased T1weighted signals in the lentiform and other nuclei. In
both Levin’s14 and our series of cases, some improvement in symptoms occurred in some patients, whether
spontaneously or because of chelation therapy is uncertain. Some differences were seen between our cases and
those of Levin’s,13,14 in that he reported myoclonus and
hypersomnia, while we did not see these in our patients.
Because MPTP toxicity and ephedronic encephalopathy were observed among drug-addicts, it is interesting to
compare the two disorders, both of which cause a parkinsonian syndrome.19 Because the euphoria-producing
substances of abuse are different, the early behavioral
alterations appear to differ in the two conditions. The
pathologic changes also are different, with MPTP damaging dopaminergic neurons and manganese, the postdopaminergic neurons. A tabulation of the clinical differences between these two types of drug-addict-induced
parkinsonism is presented in Table 4. Therapeutic response to dopaminergic agents characterizes MPTP intoxication, whereas these do not have any obvious benefit in ephedronic encephalopathy.
Acknowledgments: We thank Prof. A. Friedman, Warsaw,
Poland; Prof. G. Opala, Katowice, Poland; and Dr. J. Slawek,
Gdañsk, Poland, for their encouragement in reporting these
cases.
REFERENCES
1. Parkinson J. An essay on the shaking palsy. London: Sherwood,
Neely, and Jones; 1817.
Movement Disorders, Vol. 22, No. 9, 2007
No
Burst of energy, diminished self-criticism
Simplified speech, diminished interest in life,
features of abulia
Postural instability, spastic-hypokinetic
dysarthria
Postural instability, spastic-hypokinetic
dysarthria with subsequent development of
parkinsonism and intellectual deficit
Ineffective
2. Couper J. On the effects of black oxide of manganese when inhaled
into lungs. Br Ann Med Pharm 1837;1:41-42.
3. Edsall DL, Wilbur FP, Drinker CK. The occurrence, course and
prevention of chronic manganese poisoning. J Ind Hyg 1919;1:
183-193.
4. Canavan MM, Cobb SS, Drinker CK. Chronic manganese poisoning. Arch Neurol Psychiat 1934;32:501-512.
5. Cook DG, Fahn S, Brait KA. Chronic manganese intoxication.
Arch Neurol 1974;30:59-64.
6. Sadek AH, Rauch R, Schulz PE. Parkinsonism due to manganism
in a welder. Int J Toxicol 2003;22:393-401.
7. Herrero Hernandez E, Discalzi G, Dassi P, Jarre L, Pira E. Manganese
intoxication: the cause of an inexplicable epileptic syndrome in a 3
year old child. Neurotoxicology 2003;24(4/5):633-639.
8. Mena I, Court J, Fuenzalida S, Papavasiliou PS, Cotzias GC.
Modification of chronic manganese poisoning. Treatment with
L-dopa or 5-OH tryptophane. N Engl J Med 1970;282:5-10.
9. Fell JME, Reynolds AP, Meadow, et al. Manganese toxicity in
children receiving long-term parenteral nutrition. Lancet 1996;347:
1218-1221.
10. Masumoto K, Suita S, Taguchi T, et al. Manganese intoxication
during intermittent parenteral nutrition: report of two cases. J
Parenter Enteral Nutr 2001;25(2):95-99.
11. Ferraz HB, Bertolucci PHF, Pereira JS, et al. Chronic exposure to
the fungicide maneb may produce symptoms and signs of CNS
manganese intoxication. Neurology 1988;38:550-553.
12. Hauser RA, Zesiewicz TA, Rosemurgy AS, Martinez C, Olanow
CW. Manganese intoxication and chronic liver failure. Ann Neurol
1994;36:871-875.
13. Levin OS, Fedorova NV, Amosova NA, Shtok VN. Ephedronic
parkinsonism. Nevrologicheskyy Zhurnal 2000;2:8-15.
14. Levin OS. “Ephedron” encephalopathy. Zh Nevrol Psikhiatr Im S
S Korsakova 2005;105(7):12-20.
15. Mironenko TV. Manganese encephalopathy, neurologic aspects.
Ukrayinskyy Medychnyy Almanakh 2004;7(4) (Suppl):86-89.
16. Belhadj-Tahar H, Sadeg N. Methcathinone: a new postindustrial
drug. Forensic Sci Int 2005;153(1):99-101.
17. Ladurner G, Kalvach P, Moessler H; Cerebrolysin Study Group.
Neuroprotective treatment with cerebrolysin in patients with acute
stroke: a randomised controlled trial. J Neural Transm 2005;112:
415-428.
18. Lucchini R, Albini E, Placidi D, et al. Brain magnetic resonance
imaging and manganese exposure. Neurotoxicology 2000;21:769775.
19. Ballard PA, Tetrud JW, Langston JW: Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP): seven cases. Neurology 1985;35:949-956.
20. Yamada M, Ohno S, Okayasu I, et al. Chronic manganese poisoning: a neuropathological study with determination of manganese
distribution in the brain. Acta Neupathol 1986;70:273-278.
PARANEOPLASTIC STIFF PERSON SYNDROME
21. Mella H. The experimental production of basal ganglia symptomatology in Macacus rhesus. Arch Neurol Psychiat 1924;11:405417.
22. Olanow CW, Good PF, Shinotoh H, et al. Manganese intoxication
in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study. Neurology 1996;46:492-498.
23. Kim E, Kim Y, Cheong HK, et al. Pallidal index on MRI as a target
organ dose of manganese: structural equation model analysis.
Neurotoxicology 2005;26:351-359.
24. Newland M, Cox C, Hamada R, et al. The clearance of manganese
chloride in the primate. Fundam Appl Toxicol 1987;9:314-328.
25. Wolters EC, Huang CC, Clark C, et al. Positron emission tomography in manganese intoxication. Ann Neurol 1989;26:647-651.
26. Huang CC, Chu NS, Lu CS, Calne DB. Cock gait in manganese
intoxication. Mov Disord 1997;12:807-808.
27. Huang CC, Chu NS, Lu CS, et al. Chronic manganese intoxication.
Arch Neurol 1989;46:1104-1106.
28. Huang CC, Lu CS, Chu NS, et al. Progression after chronic
manganese exposure. Neurology 1993;43:1479-1483.
29. Rafael P. Diagnosis and treatment of manganese intoxication:
report of a case. Arch Ind Health 1957;16:64-66.
30. Mena I, Court J, Fuenzalida S, Papavasiliou PS, Cotzias GC.
Modification of chronic manganese poisoning. Treatment with
L-dopa or 5-OH tryptophane. N Engl J Med 1970;282(1):5-10.
31. Rosenstock HA, Simons DG, Meyer JS. Chronic manganism:
neurological and laboratory studies during treatment with levodopa. JAMA 1971;217:1354-1358.
32. Lu CS, Huang CC, Chu NS, Calne DB. Levodopa failure in
chronic manganism. Neurology 1994;44:1600-1602.
33. Mena I. Manganese poisoning. In: Vinkeen PJ, Bruyn GW, editors.
Handbook of clinical neurology, Vol. 36. Amsterdam: Elsevier/
North-Holland; 1979. P 217-237.
1343
GAD Antibody Positive
Paraneoplastic Stiff Person
Syndrome in a Patient with Renal
Cell Carcinoma
John C. McHugh, MRCPI,1* Brian Murray, MD,1
Radhakrishnan Renganathan, MRCPI,1
Sean Connolly, FRCPI,2 and Tim Lynch, FRCPI1
1
Department of Neurology, Mater Misericordiae University
Hospital, Dublin, Ireland; 2Department of Clinical
Neurophysiology, St Vincent’s University Hospital, Elm Park,
Dublin, Ireland
Abstract: Stiff person syndrome (SPS) is an unusual cause
of muscle rigidity and spasms. It is believed to have an
autoimmune pathogenesis and is associated with autoantibodies to glutamic acid decarboxylase (GAD). Paraneoplastic SPS (PSPS) has been described mainly in relation to
breast cancer and is associated with antibodies to amphiphysin. Few reports of PSPS document the finding of
GAD autoantibodies. We present the first reported case of
anti-GAD positive PSPS in a 53-year-old male with occult
renal carcinoma. Clinical benefit was marked following
nephrectomy and intravenous immunoglobulin treatment.
Renal carcinoma should be considered in patients with SPS.
© 2007 Movement Disorder Society
Key words: stiff person syndrome; GAD; paraneoplastic;
IVIG.
Stiff person syndrome (SPS) is an uncommon CNS
disorder comprising stiffness and spasms of axial muscles with continuous motor unit activation (CMUA), and
abnormal exteroceptive reflexes on EMG. Stiff limb syndrome (SLS) is a variant of SPS where symptoms are
disproportionate to a limb. It is believed that both disorders share an autoimmune mechanism and there is a
strong association with autoantibodies to glutamic acid
decarboxylase (GAD).1 A small proportion of cases are
considered to be paraneoplastic. The autoantibody to
amphiphysin was considered an important marker for
such cases, particularly in association with breast cancer.2 More recently, however, a number of other antibodies, including GAD, have been described in association
with paraneoplastic SPS (PSPS)/SLS and a variety of
*Correspondence to: Dr. John C McHugh, Department of Neurology, Mater Misericordiae Hospital, Dublin 7, Ireland.
E-mail: [email protected]
Received 20 November 2006; Accepted 21 November 2006
Published online 7 May 2007 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.21374
Movement Disorders, Vol. 22, No. 9, 2007