Improvement in Ephedrone Parkinsonism After Global Pallidus Pars Interna Deep Brain Stimulation Implantation

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Video 1

Preoperative and postoperative (5-month follow-up) neurological examination of the patient.

Dariusz Koziorowski MD, PhD, Stanislaw Szlufik MD, Tomasz Mandat MD, PhD, Maria Kloda PT, PhD, Karolina Duszynska-Was MA,
Agnieszka Drzewinska MA and Andrzej Friedman MD, PhD

Article first published online:  14 NOV 2015 | DOI: 10.1002/mdc3.12248


A new form of presumed manganese poisoning has been reported in drug-addicted persons from Eastern Europe and the Baltic states who have intravenously taken injections of self-prepared methcathinone hydrochloride (ephedrone), which is synthesized from a mixture of commercial cold remedy compounds containing phenylpropanolamine and acetic acid with potassium permanganate as a potent oxidant. An ephedrone-induced manganese encephalopathy underlies clinical signs of motor parkinsonism.[1] Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, as well as levodopa nonresponsive parkinsonian and dystonic syndrome resulting from manganese intoxication. The first reports describing young people who developed signs of a spastic-hypokinetic dysarthria, postural instability with falling, cock gait, parkinsonian signs (hypokinesia, hypomimia, and rigidity), bradyphrenia, hypersomnia, and myoclonus after intravenous injections of ephedrone came from Russia.[2] MRI of these patients showed a transient hyperintense T1 signal in the globus pallidus and putamen. The MRI changes may subsequently disappear, but the clinical symptoms remain unchanged. No effective treatment could have been recommended so far.[3]

Case Report

This case report describes a history of a 27-year-old woman with previous polysubstance dependence and psychiatric history, who administered self-designed ephedrone derived from Sudafed using potassium permanganate and revealed significant clinical symptoms of manganese-induced parkinsonism. As an 11-year-old teenager, she started using canabinols. Subsequently, she used to take opioids, amphetamine, benzodiazepines, and drug combinations as well. She also revealed some suicidal thoughts and attempts in the past (depression has been diagnosed and treated for 7 years). Recently, she is in a methadone program—she has been taking 100 mg/day. There were no neurological disorders in the family history.

In medical history directly previously to the neurological deficits, she started using ephedrone since January 2010. After 6 months, she developed the first neurological symptoms: dysarthria, rigidity, and bradykinesia. Typical changes in MRI examination were found: hyperintensive signals in left and right globus pallidus in T1W imaging corresponding to manganium accumulation (Fig. 1A), which disappeared 1 year later, however without the resolution of clinical symptoms (Fig. 1B). The clinical symptoms corresponded to parkinsonism with lower-limb dystonia. The neurological examination revealed strong cogwheel rigidity (in trunk and extremities), dysarthria, bradykinesia, dystonic gait (cock gait), and postural instability with falls (UPDRS III score: 48 points). There was no response to l-dopa whereas amantadine was intolerant. No cognitive impairment was found at the psychological examination. Taking into consideration the dominant symptomatology of general dystonia/parkinsonism as well as no response to l-dopa treatment, we decided that the patient can be suitable for bilateral implantation of electrodes for DBS in the globus pallidus pars interna (GPi).

Pre- and postoperative imaging

Figure 1. Pre- and postoperative imaging. (A) MR T1W imaging of the patient in a 6-month time period from the beginning of clinical symptomatology: hyperintensive signals in left and right globus pallidus: manganium accumulation. (B) MR T1W imaging of the patient in a 2-year time period from the beginning of clinical symptomatology: normal brain structures, without hyperintensity. (C) CT scan of the patient in a 5-month time period from the surgical procedure: localization of electrodes.



Stereotactic contrast CT was performed after preoperative 1.5T MRI examination. Then, MRI and CT images were fused (Stereotactic Planning Software; Brainlab AG, Feldkirchen, Germany), and the coordinates of GPi were calculated using a direct and indirect method (mid anterior/posterior commissure: x 20, y 3, z 5). Microrecording (MER) and macrostimulation were conducted using Leadpoint (Medtronic, Minneapolis, MN) followed by macrostimulation evaluated by a neurophysiologist and a movement disorders neurologist. Two microelectrodes (central, C; medial, M) were introduced and MERs were registered from −10 to +1 mm every 0.2 mm. Macrostimulation was focused on adverse effects related to the stimulation at −2, 0, and +2 from the C and M path. Motor adverse effects appeared below 2 V from the M path and visual sensations appeared below 2 V from both paths at +2 bilaterally. Under fluoroscopic guidance, microelectrodes were replaced by a permanent electrode (3387-28; Medtronic) at C path 0 bilaterally. When lateral control X-ray confirmed the location of the electrode to be identical to the microelectrode, the electrode was locked (Stimlock; Medtronic), and, during the second stage of the procedure under general anesthesia, two internal pulse generators (Activa SC 37603; Medtronic) were connected to the electrodes.

The postoperative 5-month follow-up evaluation (see Video 1) revealed significant improvement in rigidity (UPDRS-III score 15 points preoperatively vs. 2 points postoperatively) and less important in bradykinesia (UPDRS-III score 20 points preoperatively vs. 8 points postoperatively; Table 1). Slight improvement was also observed in lower-limb dystonia, gait disturbances, and postural instability (Table 1). In this case, we used a compilation of balance tests, which included four variants of the Timed “Up and go” Test, Tandem Stance Test, 180° Tandem Pivot Test (patient was asked to make a 180° twist during standing on tiptoe), and Walking Tandem Test (patient was asked to walk a 3 m distance bringing heel to toes). The results in all of the balance tests (besides Timed “Up and go” Test with beaker in the left hand) revealed improvement. The patient's saccades examination revealed a progressive standardization of all saccades' parameters (especially amplitude and velocity of the ocular movements, which were altered before the surgical procedure; Table 2). No improvement was observed in dysarthria and in autonomic symptoms. There was also no deterioration in neuropsychological tests; however, after DBS GPi implantation, during 5-month-follow-up the patient had to increase the daily dose of methadone.

Table 1. UPDRS-III part and balance tests before and after surgery
Parameter Before Surgery After Surgery
  1. a

    180° Tandem Pivot Test: 1 point = patient is able to stand but unable to start the rotation of the body standing on toes; 3 points = patient is able to initiate the rotation, but the movement is a complex rotation with possibility of stopping during the motion.

Speech 3 3
Facial expression 3 2
Tremor at rest 0/0 0/0 0/0 0/0
Action tremor 0 0 0 0
Rigidity 3/3 3/3 0/0 0/0
Neck rigidity 3 2
Finger taps 2 2 1 1
Hand movements 2 2 1 1
Rotation of the hands and forearms 2 2 0 0
Leg agility 2 2 1 1
Rising from chair 1 0
Posture 2 0
Gait 2 0
Postural stability 2 1
Bradykinesia 4 2
Total UPDRS-III score 48 points 16 points
Balance tests
Timed “Up and go” Test 12.89 sec 9.46 sec
Timed “Up and go” Test (+ counting) 14.95 sec 10.05 sec
Timed “Up and go” Test (+ beaker in RL) 13.83 sec 11.02 sec
Timed “Up and go” Test (+ beaker in LL) 10.97 sec 11.19 sec
Tandem Stance Test 8 sec 10 sec
180° Tandem Pivot Testa 1 point 3 points
Walking Tandem Test 18.50 sec 16.22 sec

Table 2. Saccadometric analysis before and after surgery

  Before Surgery After Surgery
Average (±) Average (±)
All Responses
Duration [ms] 49.1 12.0 38.3 7.5
Latency [ms] 129.7 14.1 140.7 36.0
Amplitude [°] 772.0 347.5 7.9 1.6
Peak velocity [°] 33,381.0 9,169.9 456.4 51.8
Left Responses
Duration [ms] 60.3 5.5 47.1 3.9
Latency [ms] 135.1 17.2 170.0 26.7
Amplitude [°] 1,067.1 269.7 9.7 0.9
Peak velocity [°] 35,803.6 11,813.8 472.7 71.3
Right Responses
Duration [ms] 37.5 2.9 33.1 3.3
Latency [ms] 124.7 6.3 119.5 15.9
Amplitude [°] 476.3 43.3 6.9 0.7
Peak velocity [°] 31,000.0 4,365.2 447.7 30.6

Five months after the implantation, neurological symptoms are stable with the DBS parameters set on (both stimulators): contacts C(+) 0(−) 1(−), pulse duration 120 ms, frequency 180 Hz, amplitude left 2.1 V, and amplitude right 2.1 V. There were no serious adverse events observed since the time of DBS implantation.


To our knowledge, this is the first study describing DBS surgery in an EP patient. There is increasingly growing evidence suggesting that GPi DBS can be effective in patients with idiopathic or inherited generalized dystonia.[4, 5] On the other hand, there is comparatively less experience about the effects of GPi DBS on acquired dystonia and dystonia-parkinsonism symptoms.[6, 7] GPi is a crucial point for pathogenesis of EP.[8] Hyperintense Tl signal in the globus pallidus usually disappears in further observation, but the clinical symptoms remain unchanged.[8] The precise mechanism of manganium short- and long-term toxicity on basal ganglia and other brain structures still remains unclear because of the lack of neuropathological studies.[9] Most EP patients show slow and hypometric horizontal saccades, an increased occurrence of square-wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and more errors than controls in mixed pro- and antisaccades' tasks.[10] In our patient, we observed a serious improvement in most parameters of saccadic evaluation: latency, amplitude, and peak velocity (Table 2). It can be a result of general improvement of parkinsonian features in our patient.


Regarding the fact, that so far there is no recommended method of treatment in EP, in our opinion, GPi DBS should be also taken into consideration as a method of treatment in EP-dystonia syndromes.

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