Letters to the Editor Related to New Topics
Implantation of the Nucleus Tegmenti
Pedunculopontini in a PSP-P Patient: Safe
Procedure, Modest Benefits
Video
The identification of some degree of gait impairment amelioration and cognitive benefits in patients with Parkin-son’s disease (PD) implanted in the nucleus pedunculopon-tine (PPN)1,2 suggested us to investigate to what extent a
similar approach might be useful in a patient affected by pro-gressive supra-nuclear palsy (PSP).3
The case was a 70-year-old man who manifested walking impairment and asymmetrical rigidity at 67 years of age. At 69, freezing of gait (FOG), postural instability, and vertical supra-nuclear palsy dominated the clinical syndrome. When admitted to the University of Tor Vergata Neurology Depart-ment he was under 300 mg levodopa/carbidopa (mean benefit <20%; neither increased response with challenge test at max-imal dose was detected nor a prolonged chronic therapy with higher dose up to 800 mg was effective), 75 mg venlafaxine and benzodiazepines at night. Neurological examination showed vertical supra-nuclear palsy (although not yet severe), trunk akinesia, rigidity of neck, postural instability, reduced verbal fluency, dysarthria, and occasional impairment of swallowing. Modest cognitive impairment was detected. MRI showed mesencephalic atrophy (‘‘tegmental midbrain’’ below 70 mm2); standard FDG-PET confirmed the expected pattern
of reduced metabolic activity in the basal ganglia, prefrontal and cingulated cortex (Supporting Information Fig. 1). Over-all, he was given a diagnosis of PSP-P.3
For neurosurgical details, consider that the unconven-tional ‘‘direct’’ determination of brainstem targets4 allowed the previously defined PPN1,2 to be renamed as its caudal representation, the nucleus tegmenti pedunculopontini (PPTg). It should be underlined that the present target has nothing in common with the so-called PPD, which lies well lateral to the lemniscus medialis. The displacement of the catheter tip from the midline (about 7.2 mm, refer Support-ing Information Fig. 2) may appear slightly more anterior and lateral from the ‘‘ideal’’ location5 but takes into account safety reasons, specifically we were careful to avoid crossing STN and sub-nigral areas in a severely atrophic brain; only a single Medtronic 3389 was
posi-tioned in the right PPTg. In addition, the trajectory4avoids trans-ventricular approach and minimizes the risk to dam-age cranial nerves.
Clinical post-surgery evaluations (at 4, 6, and 9 months) included UPDRS following drug night withdrawal (CAPIT) and under L-dopa administration, neuropsychological testing in CAPIT and a synthesized version of the Giladi question-naire6(the latter maintaining stable DBS and drugs treatment for at least 1 month). Conventional 18F-FDG (200 MBq) was also performed in the postsurgery phase; analysis utilized the PMOD Brain Database Tool (PMOD Technologies, Adliswil, Switzerland) and FDG PET data were spatially normalized using the methodology and the standard PET template of SPM99.7
The patient did not manifest any adverse events in the condition PPTg-ON (25 Hz), apart from contra-lateral pares-thesia, which was reversible in a few minutes provided the STIM voltage was kept<3.4 V. The global UPDRS section III improvement, in CAPIT, was modest (scores of 22 and 18 in OFF-DBS and ON-DBS, respectively, equivalent to 18%, Table 1A) under the best STIM combination (low bipolar contacts). Analogous evaluation under the L-dopa morning dose did not differ (not shown). Gait was improved only in terms of a consistent amelioration of the primary gait ignition failure (Table 1A). On the other hand, the impact on postural stability and direction changes was absent. When evaluated with a specific questionnaire as the Giladi for FOG (adapted from 6) DBS-mediated effect were modest (Table 1B). No DBS-related effect could be detected in non-motor domains (such as dysphagia and swallowing impairment). Neuropsychological tests did not reveal major cognitive changes apart from minimal improvement in verbal fluency (Table 1C).
The observed response (slight changes on non-motor and motor domains, negligible on FOG) and the cognitive profile were unimpressive. While the cognitive beneficial impact of PPTg-DBS was a consistent observation in PD, as revealed by working memory changes and grammar expression,2 PPTg-DBS did not reveal a significant impact on cognitive domains in our PSP-P patient (probably for the different ana-tomopathologic substrate, with a more pronounced and dif-fuse neuro-degeneration in PSP patients in comparison to PDs). Mistargeting, a potential cause of these negative results, is rather unlikely, since in our hands the switch ON of the same targeted area (PPTg-ON) promoted large meta-bolic brain changes in idiopathic patients with PD,8not repli-cated in this PSP case.
Although this single case seems not to support the PPTg implantation as a critical therapeutic option for PSP-P patients, at least in advanced ones, it is possible that larger trials, centred either on PSP-P recruited at the disease onset or on PSP Richardson type, will verify further the potential of DBS-mediated stimulation to activate directly surviving fibres or even delay the disease evolution.
Additional Supporting Information may be found in the online version of this article.
Potential conflict of interest: No conflict of interest is applicable to the authors concerning the manuscript.
Published online 11 August 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22706
Legends to the Video
Segment 1. shows the patient motor assessment in the PPTg-OFF condition.
Segment 2. shows the patient motor evaluation during the PPTg stimulation. No substantial motor amelioration was achieved by switching on the stimulator.
Acknowledgments: This manuscript received financial support from the institutional grants (Min della Salute/PRIN to A.S., and Regione Sicilia and Min della Salute to P.S.). We
are profoundly grateful to Dr. Paolo Mazzane, whose neurosur-gical expertise made possible the implantation in our patient.
Author Roles: Brusa Livia: study design and neuro-psy-chology; Ceravolo Roberto: study design and neuro-radiology; Galati Salvatore: clinical follow-up of the patient and editing the manuscript; Moschella Vincenzo: motor evaluations (blind scores); Marzetti Francesco: motor evaluations (blind score); Iani Cesare: counseling; editorial revision; Stanzione Paolo: co-leader of the project and neuropsychology; Stefani Alessan-dro: project responsible; writing the manuscript.
TABLE 1. Clinical assessments performed before and after PPTg surgery in a PSP-P patient
A. UPDRS (section I–III) and selected items (27–30), in CAPIT
Pre-surgery PPTg-OFF
PPTg-ON (3.4 V) at 3 moa 6 Mo follow-up 9 Mo follow-up
31/22 11/02 Case1/02 11/02
UPDRS
I/II (1–17) 22 21 21 20b 21 21 23
III (18–26) 22 22 21 18c 20 19 20
27. Arising from chair 3 2 2 1 2 1 2
28. Posture 2 2 2 2 2 2 2
29. Gait 3 2 2 1 2 2 2
30. Postural stability 2 3 2 2 3 2 2
31. Body bradykinesia and hypokinesia 2 2 2 2 2 2 2
Total 27–31 12 11 10 8 11 9 10
B. FOG-Q (adapted from Ref. 6): selected itemsd
Pre-surgery PPTg-OFF PPTg-ON
A 1.1 3 3 3
A 1.3 3 2 2
A 1.12 3 3 3
A 1.13 3 3 3
Total 12 11 11
C. Cognitive tests, in CAPIT
Pre-surgery PPTg-Off PPTg-ON
California short re-call 25 24 29
California delayed re-call 3 4 6
FAS 11 14 8
Digit verbal span foreward 6 5 5
Digit verbal span backward 2 2 2
Trail making A 50 63 55
Trail making B 180 175 135
Trail making B-A 130 112 80
Motor clinical evaluations (UPDRS section III) were executed in the morning, in CAPIT condition at 4–6–9 mo following the surgery comple-tion, in different setting parameters: OFF-DBS, ON-DBS bipolar lower contacts, ON-DBS bipolar upper contacts, ON-DBS monopolar. We also studied the best DBS protocol under ON-treatment condition, but no significant differences was found (data not shown). Pharmacological therapy had been maintained stable since the day preceding each clinical testing day. All motor evaluations were realized, with 1 wk interval, with a rand-omised sequence, by expert neurologists blind to the DBS condition.
For neuropsychological tests, the patient was submitted to two different sections of evaluation, executed in the morning, in CAPIT, with 1 mo interval, and with a randomized sequence. On one of the two testing days PPTg-DBS was permanently on (in the best DBS setting condition) for at least 12 hr; on the second testing day PPTg-DBS was off for at least 12 hr prior to the evaluation (PPTg-OFF). The neuropsychologist and the patient were blind to the DBS condition (PPTg-ON vs. PPTg-OFF). Re-tests were performed using test parallel forms to avoid learning-related phenomena. The order of presentation of the parallel forms was appropriately counter-balanced.
aTo note, none of the other occasionally tested protocols (mono polar STIM or 50/70/130 Hz or even 4–4.5 V) provided better results. b
Better turning in bed, nighttime, with respect to PPTg-OFF condition. c
Improved rigidity (left arms) and slightly improved finger tapping, bilaterally, with respects to PPTg-OFF. d
Livia Brusa, MD, PhD Cesare Iani, MD Ospedale S. Eugenio UOC Neurologia Rome, Italy Roberto Ceravolo, MD Dipartimento di Neuroscienze Clinica Neurologica Universita‘ di Pisa Pisa, Italy Salvatore Galati, MD Vincenzo Moschella, MD Francesco Marzetti, MD Clinica Neurologica Universita’di Roma Tor Vergata Rome, Italy IRCCS Fondazione S. Lucia Rome, Italy Paolo Stanzione, MD Alessandro Stefani, MD* Clinica Neurologica Universita di Roma Tor Vergata Rome, Italy IRCCS Fondazione S. Lucia Rome, Italy *E-mail: stefani@uniroma2.it
References
1. Stefani A, Lozano AM, Peppe A, et al. Bilateral deep brain stimu-lation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain 2007;130:1596–1607.
2. Zanini S, Moschella V, Stefani A, et al. Grammar improvement following deep brain stimulation of the subthalamic and the pedunculopontine nuclei in advanced Parkinson’s disease: a pilot study. Parkinsonism Relat Disord (in press).
3. Williams DR, De Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progres-sive supranuclear palsy: Richardson’s syndrome and PSP-parkin-sonism. Brain 2005;128:1247–1258.
4. Mazzone P, Sposato S, Insola A, Di Lazzaro V, Scarnati E. Ste-reotactic surgery of nucleus tegmenti pedunculopontini. Br J Neu-rosurg 2008;22:S33–S40.
5. Zrinzo L, Zrinzo LV, Tisch S, et al. Stereotactic localization of the human peduncolopontine nucleus: atlas-base coordinates and validation of a magnetic resonance imaging protocol for direct localization. Brain 2008;131:1588–1598.
6. Giladi N, Shabtai H, Simon ES, Biran S, Tal J, Korezyn AD. Construction of freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Relat Disord 2000;6:165–170. 7. Ceravolo R, Borghetti D, Kiferle L, et al. CSF phosphorylated
TAU protein levels correlate with cerebral glucose metabolism assessed with PET in Alzheimer’s disease. Brain Res Bull 2008;76:80–84.
8. Stefani A, Ceravolo R, Brusa L, et al. Non-motor functions in Par-kinsonian patients implanted in the pedunculopontine nucleus: focus on sleep and cognitive domains. J Neurol Sci. (in press).
Amelioration of Subacute Camptocormia
in Multiple System Atrophy
by Protirelin Tartrate
Camptocormia (CC) describes a severe forward flexion at the waist, which disappears in the recumbent position but increases while standing.1CC may be associated with various etiologies1such as parkinsonism [Parkinson disease, multiple system atrophy (MSA)], dystonia, spine deformities, stroke, focal myopathy, amyotrophic lateral sclerosis (ALS), and metabolic and psychogenic disorders.
Protirelin tartrate (PT) has been in the Japanese market, mainly being used for many ataxic diseases2such as familial spinocerebellar degeneration or MSA, and its mechanism has been reported to regulate excitatory amino acids3 or glucose metabolism in cerebellar ataxia.
Here, we report a patient with MSA whose CC showed subacute onset and unexpected alleviation by treatment with PT which was given to treat cerebellar ataxia.
This 68-year-old woman presented with 7-year history of parkinsonism, ataxia, and polyuria associated with subacute onset of stooped posture. She had developed mild flexed posture of about 158 of inclination at the waist 5 months ago. She received levodopa (400 mg/day), trihexyphenidyl hydrochloride (4 mg/day), but the response was poor. Her spine bent rapidly deteriorated to 458 a few days prior to admission.
On examination, she had a mask-like face, hoarseness, weakness and spasticity of lower extremities, rigidity of the upper extremities, action tremor of the hands, limb and trun-cal ataxia, polyuria, and stooped posture. She was diagnosed to probably have MSA based on the criteria by Gilman et al.4She was able to lie flat on recumbent position, and she resumed a flexed posture of about 458 on walking (Fig. 1A). Laboratory tests showed normal muscle enzymes. Cerebral magnetic resonance imaging (MRI) showed high signal inten-sity at the lateral putaminal rim, and mild cerebellar and pon-tine atrophy. MRI of paraspinal muscles showed no signal abnormality.
PT (1 mg in 100 mL) in saline (100 mL/30 min) was injected to treat cerebellar ataxia, but CC was significantly alleviated by 2-day treatment with PT against our expectation (Fig. 1B).
Then we assessed the CC by video image, and we used electromyography of the abdominal and paraspinal muscles to analyze the pathophysiological condition of CC. PT was stopped on day 3 to confirm the effect of PT. CC reappeared on the same day (Fig. 1C). PT was resumed, and the patient’s CC improved on that same day (Fig. 1D). The volt-age of the paraspinal muscles showed low-voltvolt-age amplitude after stopping PT (Fig. 1E), which increased after resuming PT (Fig. 1F).
We speculated that the improvement of deficiency of spi-nal motoneurospi-nal excitability of the paraspispi-nal muscles might
Published online 30 July 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22699
be the most likely mechanism in the amelioration of CC in our case, not focal dystonia or focal myositis, because they showed spasticity of the lower extremities, a rapid response to PT, and increased voltage in the paraspinal muscles in par-allel with improvement of CC.
PT modifies the contractile response of flexor and extensor muscles acting on the spinal motoneuronal pool.5PT counter-acts the deficiency of spinal motoneuronal excitability by regulating dopaminergic neurotransmission.6The effect of PT on spinal motoneurones has been reported to develop rapidly, within 1 hour.7 For this effect, PT has been reported to improve spasticity and weakness in patients with ALS.7
This case suggests that PT could be an effective treatment for subacute CC in patients with MSA. These results await further confirmation in a larger patient cohort.
Asako Takei, MD* Shinsuke Hamada, MD Sanae Homma, MD Keiko Hamada, MD Kunio Tashiro, MD, PhD Takeshi Hamada, MD
Hokuyukai Neurological Hospital Sapporo, Japan *E-mail: atakei@med.hokudai.ac.jp
References
1. Azher SN, Jankovic J. Camptocormia: pathogenesis, classification, and response to therapy. Neurology 2005;65:355–359.
2. Sohue I, Takayanagi T, Nakanishi T, et al. Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations. J Neurol Sci 1983;61:235–248.
3. Miyamoto Y, Kikakawa R, Hatanaka I, et al. Thyrotropin-releas-ing hormone reduces myo-inositol contait in rat cerebellum pre-treated with lithium. J Neurochem 1987;49:88–91.
4. Gilman S, Low PA, Quinn N, et al. Consensus statement on the diag-nosis of multiple system atrophy. J Neurol Sci 1999;163:94–98. 5. Delwaide PJ, Schoenen J, Dubois V, Belgium L. Thyrotropin
releas-ing hormone (TRH) increases excitability of human motoneurons as tested by the F wave. Neurology 1984;34 (Suppl 1):284.
6. Raffaele R, Consentino E, Anicito MB, et al. Effects of TRH-T on spinal motoneurones in man. Neuropharmacol Neurotoxicol 1992;3: 1017–1018.
7. Mitsumoto H, Salgado ED, Negroski D, et al. Double-blind, cross-over trials with chronic, subcutaneous injections of small doses of TRH in patients with ALS. Neurology 1985;35 (Suppl 1):71. FIG. 1. (A) Before treatment. (B) After treatment. (C) After stopping PT. (D) After resuming PT. (E,F) EMG of the rectus abdominals and L2 paraspinal muscles; (E) After stopping PT. (F) After resuming PT.
Transient Improvement of Psychogenic
(Proprio-)Spinal-Like Myoclonus to Electrical
Nerve Stimulation
Video
With great interest, we read a letter by Malteˆte et al.1on pro-priospinal myoclonus (PSM) and transcutaneous electrical nerve stimulation (TENS) that discusses neuromodulatory and psychological effects. We report two patients with (pro-prio-)spinal-like myoclonus with transient response to electri-cal nerve stimulation and mainly features of a psychogenic origin.
A 60-year-old man with a sensomotor L2-4 syndrome developed jerks of the right leg that increased during stand-ing and walkstand-ing and decreased while lystand-ing. The patient could not walk without assistance. Clonazepame, primidone, and carbamazepine had no effect. As the patient experienced jerk suppression by touching his skin in the L2-4 dermatome. TENS (71 mA, 60Hz and 350 microseconds) was applied there proposing a neuromodulatory effect on a segmental myoclonus generator. Standing and walking improved. How-ever, stimulation strength had to be increased within a few months. The patient developed skin reactions to the surface electrodes. TENS was replaced by direct stimulation of the cutaneus femoris lateralis nerve with a positive effect on standing abilities. After 6 months, clinical appearance gener-alized and the patient developed additional tremor. He was clinically reevaluated. Motor evoked potentials (MEP) and needle electromyography (EMG) were normal. Surface poly-electromyography (spEMG) revealed myoclonic jerks of 200–600 ms length during standing and walking. Addition-ally there was an irregular about 5 Hz resting and postural tremor of the right arm and tremor periods of the right leg without temporal correlation between arm and leg. Neither was there a fixed temporal or spatial muscle recruitment pat-tern of intermittent leg myoclonic jerks which should be the case in PSM. Brain MRI and long-loop reflexes (LLR) were normal. Jerk-locked-back-average electroencephalography (JLBA-EEG) showed no premyoclonic sharp waves or spikes but a contralateral central-paramedian negativity (readiness potential, RP) 1 second before movement of the right tibialis anterior muscle. Magnetoencephalography revealed a contra-lateral central dipole around 250 ms preceding rhythmic tremor and myoclonic burst activity.
The second case was a 49-year-old man with lower back pain and symmetric dorsal-thoracic and lumbar jerks that had started suddenly after lifting a heavy object.
Jerks involved back muscles while lying and sitting with additional tremorous activity of proximal leg muscles when standing and walking. Spine MRI showed a disc protrusion with slight affection of the left L1 root. Cranial MRI, labora-tory testing, MEP, somatosensory evoked potentials,
electro-neurography, and LLR were normal. EMG showed positive sharp waves and fibrillation potentials in left L5/S1 muscles.
spEMG in sitting position revealed jerks of 500 millisec-ond every 3 secmillisec-onds with decrease of frequency after a few minutes and during attention distraction. Atypical for PSM conduction velocity between recruited trunk muscles was faster than 10 m/s. While standing upper leg muscles were irregularly involved but not simultaneously bilaterally recruited. JLBA-EEG showed no pre-myoclonic spikes but a RP beginning >1 second before movement onset. Clonaze-pame, valproat, primidone, and piracetame had no effect. TENS (>2 mA, 60 Hz, 450 microsecond) of the L3-S1 der-matome was associated with a subjective electrical sensation and relief of lumbar pain. Myoclonus and gait unsteadiness were relieved by TENS but only for a few days.
Changes in clinical occurrence and muscle recruitment, gait unsteadiness without falling, different jerk patterns during lying and standing, sudden onset, slowing of inter-jerk-interval when sitting for longer periods, jerk pauses during distraction and ongoing legal proceedings to obtain invalidity pensions were suspicious of a psychogenic origin in our patients. Jerks were mostly action induced and settled with rest which is the opposite to the pattern of occurrence of PSM. EMG jerk pat-terns were irregular and exceeded length and muscle recruit-ment velocity of a PSM. The RP indicated a voluntary move-ment aspect. TENS showed transient effects and was associ-ated with a subjective electrical sensation. In contrast to the report by Malteˆte et al.1 antimyoclonic threshold increased over time. Thus, we consider a placebo effect in our patients. We initiated psychotherapy which is ongoing.
In PSM, it has been reported that even more typical clini-cal features and polymyographic patterns than in our patients can be mimicked voluntarily2 and also occur in psychogenic myoclonus.3
We therefore conclude that placebo effects of TENS on myoclonus should generally be taken into account especially because of the highly suggestive procedure and its elicited electrical sensations.
Legends to the Video
Segment 1. Patient one with irregular jerks mainly of the right leg. Without TENS he is only able to stand and walk with assis-tance but does not fall (segment one). Improved walking and standing abilities with TENS of the upper right leg (segment two). Segment 2. Patient two with different jerk patterns and fre-quencies. During standing involvement of leg muscles, during sitting and lying slow lumbar jerks (segment three). Improved standing abilities with TENS of the left upper leg as well as decreased jerks when sitting and lying (segment four).
Acknowledgments: All authors are employed at the Hein-rich-Heine-University, Du¨sseldorf. Lars Wojtecki: Expert Testimony, Local german law court; Contracts and other, honoraria for lectures from Valeant/Meda, Boehringer, Ceph-alon-Pharma, TEVA. Christian Wille: Contracts and other, invited lectures from Medtronic Inc., ANS Division of St. Jude Medical, Cephalon GmbH Germany; Travel support from Medtronic Inc., ANS Division of St. Jude Medical, Cephalon GmbH Germany, Olympus, Germany. Jan Vesper: Contracts and other, sponsorship for meetings, ANS Division of St. Jude Medical, Medtronic. Alfons Schnitzler: Advisory
Potential conflict of interest: Jan Vesper and Christian Wille report to have received travel support and sponsorship for meetings from ANS Division of St. Jude Medical. All other authors report no possi-ble conflict of interest related to research covered in this article.
Published online 30 July 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22710
Boards, Scientific advisory boards of Pitie Salpetriere, Novar-tis, UCB, and Cephalon; Honoraria Grants, Research grants from the DFG, BMBF, Helmholtz Society, and Volkswagen Foundation; Contracts and other, honoraria for lectures from Boehringer Ingelheim, Novartis, UCB, and TEVA.
Lars Wojtecki, MD* Stefan Groiss, MD Institute of Clinical Neuroscience and Medical Psychology, Center for Movement Disorders and Neuromodulation, Heinrich-Heine-University, Du¨sseldorf, Germany Department of Neurology, Center for Movement Disorders and Neuromodulation Heinrich-Heine-University Du¨sseldorf, Germany *E-mail: schnitza@uni-duesseldorf.de Dag Scherfeld, MD Philipp Albrecht, MD Department of Neurology, Center for Movement Disorders and Neuromodulation Heinrich-Heine-University Du¨sseldorf, Germany Bettina Pollok, PhD Saskia Elben, MSc Institute of Clinical Neuroscience and Medical Psychology, Center for Movement Disorders and Neuromodulation, Heinrich-Heine-University, Du¨sseldorf, Germany Christian Wille, MD Jan Vesper, MD Department of Stereotactic and Functional Neurosurgery Center for Movement Disorders and Neuromodulation Heinrich-Heine-University Du¨sseldorf, Germany Alfons Schnitzler, MD Institute of Clinical Neuroscience and Medical Psychology, Center for Movement Disorders and Neuromodulation, Heinrich-Heine-University, Du¨sseldorf, Germany Department of Neurology Center for Movement Disorders and Neuromodulation Heinrich-Heine-University Du¨sseldorf, Germany
References
1. Maltete D, Verdure P, Roze E, et al. TENS for the treatment of propriospinal myoclonus. Mov Disord 2008;23:2256–2257. 2. Kang SY, Sohn YH. Electromyography patterns of propriospinal
myoclonus can be mimicked voluntarily. Mov Disord 2006;21: 1241–1244.
3. Williams DR, Cowey M, Tuck K, Day B. Psychogenic propriospi-nal myoclonus. Mov Disord 2008;23:1312–1313.
Head Drop in an Elder Parkinson’s Disease
After Development of Myasthenia Gravis
Dropped head is characterized by hyperflexion of cervical spine with the chin tilted toward the chest. It may be related to weak neck extensors due to neurogenic, neuromuscular, myopathic origin, or increased tone of flexor muscles (ante-collis) associated with dystonia or Parkinson’s disease (PD).1
We describe a patient with left occipital neuralgia and PD who later developed progressive head drop due to myasthenic weakness of isolated neck extensor muscles.
An 84-year-old man had a 4-year history of PD, hypothyr-oidism, hypertension, and left occipital neuralgia. His occipi-tal neuralgia was aggravated by laying his head on a cushion, extending his neck or any smooth touch on his left temporo-occipital scalp. Diagnosis was confirmed with positive nerve block. Pain was 70% controlled with Topiramate and indo-methacin. On admission, he complained of difficulty in look-ing at the mirror while shavlook-ing, trouble looklook-ing straight, and progressive neck flexion for the past 3 months. Concomi-tantly, he noted a progressive decline in his head and neck pain. He denied any trauma, diplopia, dysphagia, weakness, sensory deficit, worsening of parkinsonism, or other neuro-logical symptoms. Neuroneuro-logical examination revealed neck extensor muscles strength of 2/5 according to the Medical Research Council’s score while all the remaining muscles scored 5/5. Deep tendon reflexes were symmetric and nor-moactive. Mild resting tremor, rigidity, and bradykinesia were observed in the right hand. Posture was anteroflexed with severe antecollis. Brain MRI revealed nonspecific milli-metric ischemic gliotic changes in bilateral periventricular white matter. Cervical and thoracic magnetic resonance imaging disclosed spondylotic and degenerative vertebral changes. Electrophysiological studies revealed mild distal symmetric mixed polyneuropathy, without any sign of radicu-lopathy, myopathy, dystonia, or motor neuron diseases.
Repetitive nerve stimulation (RNS) of the facial and ulnar nerves was performed at 2, 3, and 5 Hz by recording from the left orbicularis oculi (OO) and abductor digiti minimi (ADM) muscles.2 RNS was normal at both OO and ADM
muscles. For further diagnostic evaluation, a single-fiber electromyography study was performed at the left frontalis muscle during voluntary contraction. Twelve of 20 fiber potential pairs exceeded the normal jitter (maximum 294ls, minimum 26ls) and three pairs were blocked. In addition, the mean-consecutive-difference was 92 ls and exceeded the normal limits.2 The intramuscular administration of 0.5 mg neostigmine caused a clear improvement within 30 minutes (Fig. 1). Antiacetylcholine receptor antibodies were negative. Thorax computed tomography was negative for thymoma. Routine blood tests, vasculitis markers, thyroid function tests, and a paraneoplastic panel were within nor-mal limits. Myasthenia gravis (MG) was diagnosed. Pyri-dostigmine (60 mg orally four times daily) was started. He became able to function in his daily life without difficulty for the next 9 months.
Potential conflicts of interest: The authors report no conflict of in-terest or financial disclosure.
Published online 30 July 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22704
Our patient first presented with left occipital neuralgia 4 years ago. Three months before admission, he noticed a pro-gressive head drop. Concomitantly, his neuralgiaform pain progressively subsided, and neuropathic pain medications were tapered. In a cadaver study, Hunter and Mayfield3 remarked that the greater occipital nerve may be compressed between the posterior arch of atlas and the lamina of the axis. We believe that entrapment of the greater occipital nerve by the trapezius and semispinal muscles were reduced by the development of antecollis.
Head drop may be due to antecollis in PD, myopathy, my-ositis, cervical radiculopathy, motor neuron disease, neuro-muscular joint disease, and musculoskeletal diseases.1 Suba-cute progressive antecollis has been found to be related to parkinsonian posture in 5.3% of patients with PD.1There are reports of amelioration or improvement of dropped head with levodopa, but development or exacerbation has been found with dopamine agonists.4 Disproportionate antecollis is reported in Multiple System Atrophy patients due to dysto-nia.5 However, our patient’s neck was free to passive neck movements, no dystonia was noted from electrophysiological studies, and symptoms of PD were well controlled. We excluded musculoskeletal disorders with a normal physical examination and imaging methods. Hypothyroidism has been reported in the pathogenesis of cervical neck muscle myopa-thy and antecollis.6 Our patient’s thyroid hormone levels were normal under treatment. Myopathy, radiculopathy, and motor neuron diseases were excluded with electrophysiologi-cal studies. A positive anticholinesterase test, increased jitter in single-fiber electromyography, and no electrophysiological sign of other motor unit diseases led us to diagnose a neuro-muscular junction disease. Although neck muscles may be involved in MG, isolated head drop is as an unusual present-ing symptom of MG. Besides, myasthenic involvement of the extensor neck muscles has been reported to be an unrecog-nized cause of head drop in patients with PD.7
In conclusion, MG should be considered as a differential diagnosis in patients with PD and head drop. Concomitantly,
occipital neuralgia aggravated with neck extension can be relieved by antecollis. Anticholinesterase treatment may increase the quality of life, and diagnosis of MG may decrease morbidity and mortality.
Author Roles: Research Project: Conception, Organiza-tion, Execution; Manuscript: Writing of the First Draft, Review and Critique: Isin Unal-Cevik; Research Project: Electrophysiological Studies; Manuscript: Review and Cri-tique: Cagri Mesut Temucin.
Isin Unal-Cevik, MD, PhD* Department of Neurology Ufuk University Faculty of Medicine Ankara, Turkey *E-mail: isin.unalcevik@gmail.com Cagri Mesut Temucin, MD, PhD Hacettepe University Institute of Neurological Sciences and Psychiatry Ankara, Turkey
References
1. Fujimoto K. Dropped head in Parkinson’s disease. J Neurol 2006; 253(Suppl 7):VII21–VII26.
2. Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome: summary statement. Muscle Nerve 2001;24:1236–1238.
3. Hunter CR, Mayfield FH. Role of the upper cervical roots in the production of pain in the head. Am J Surg 1949;78:743–751. 4. Suzuki M, Hirai T, Ito Y, et al. Pramipexole-induced antecollis in
Parkinson’s disease. J Neurol Sci 2008;264:195–197.
5. van de Warrenburg BP, Cordivari C, Ryan AM, et al. The phe-nomenon of disproportionate antecollis in Parkinson’s disease and multiple system atrophy. Mov Disord 2007;22:2325–2331. 6. Askmark H, Olsson Y, Rossitti S. Treatable dropped head
syn-drome in hypothyroidism. Neurology 2000;55:896–897.
7. Fasano A, Evoli A, Piano C, Tonali PA, Bentivoglio AR. Myas-thenia gravis: an unrecognized cause of head drop in Parkinson’s disease. Parkinsonism Relat Disord 2008;14:164–165.
FIG. 1. (a) Prominent antecollis in a patient diagnosed with Parkinson’s disease; (b) Resolution of head drop after administration of anticholines-terase therapy.
Goal Attainment After Treatment
of Parkinsonian Camptocormia with
Botulinum Toxin
We respond to the article of von Coelln et al.1and the letter of Colosimo and Salvatori2 who reported ultrasound-guided and CT-guided injection of iliopsoas muscle with botulinum toxin in 4 and 2 patients with parkinsonism and camptocor-mia, respectively. We can confirm their results in a goal attainment controlled study in 10 patients using a different preparation of botulinum toxin.
Camptocormia has various etiologies, but occurs most of-ten in patients with Parkinson’s disease, although its fre-quency of occurrence is higher in MSA.3Dystonic and
myo-pathic pathologies have been suggested.4,5 Camptocormia
cannot be correlated to the akinesia, and does not respond regularly to dopaminergic treatment, while physiotherapeutic approaches can be helpful to the patient. So far, there have been only few reports on the use of botulinum toxin in camp-tocormic patients.1,2,6 A standardization of target muscles, applied doses, or control of injection has not been achieved to date.
To determine the effectiveness of botulinum toxin injec-tions for camptocormia, we treated 10 patients after having determined their subjective treatment goals and evaluated goal attainment after 3 weeks. Goals could be set on any of the three levels of disability of the international classification of functioning, i.e., impairment, activity limitations, or partic-ipation restrictions. Patients could choose to set one, two, or three goals. After 3 weeks, the treating physician and the patient evaluated treatment success on a scale from 22 to 2. We calculated the T-Score for every patient.7 Treatment
goals were a more upright gait (N5 6), pain relief (N 5 3), grasping of items that were out of reach (N 5 3), to allow easier participation, e.g., shopping or sports (N 5 2), and less stigmatization (N 5 3). According to their clinical appearance, the patients were treated bilaterally in rectus ab-dominis muscles or ilio-psoas muscles, depending on whether we saw predominant hip or lower trunk flexion, respectively. Patients were treated open-labeled with 100–300 U (mean dosage 2106 50 U) botulinum toxin type A (Xeomin). Intra-muscular injections were applied with a maximum dose of 50 U per site and controlled with ultrasound-guidance. The iliopsoas muscle was injected directly below the inguinal lig-ament with two to three sites. The two subgroups rectus ab-dominis vs. iliopsoas were compared using Student’s t-test. For the patient group characteristics see Table 1.
After 3 weeks, we did not see a significant goal attain-ment. Not a single patient fully reached any therapy goal although muscular atrophy in the injected muscles was ascer-tained by ultrasound examination. Two patients reported mildly sore belly muscles occurring 1 week after injection and lasting for about 2 weeks. Thus, botulinum toxin in mean dosages of 210 U is not an adequate treatment for
camptocormia, and did not fulfill the expectations of the patients or of the treating physician.
This negative finding is in line with the previous reports,1,2 and can be attributed to the complex axial disorder involving other muscles and/or the deep portions of the iliopsoas that were not reached with the subligamental approach used here. Alternatively, overactive abdominal wall and/or iliopsoas muscles are not a main cause of camptocormia in parkinson-ism. It could also be due to an inappropriate low dosage of botulinum toxin to produce a clinically discernible effect. However, this is unlikely, as substantial atrophy of the injected muscles could be documented using sonography.
We feel that the treatment of camptocormia in parkinso-nian patients remains a domain of physiotherapy. The man-agement should include the adequate supply with mobile aids to support the patients’ verticalization, such as high walking frames with forearm support.
Urban M. Fietzek Frauke E. Schroeteler Andres O. Ceballos-Baumann* Neurologisches Krankenhaus Mu¨nchen, Scho¨n Kliniken, Center for Parkinson’s Disease and Movement Disorders, Parzivalplatz 4, Munich, Germany *E-mail: andres.ceballos-baumann@nk-m.de Acknowledgments: This work was supported by Merz Pharmaceuticals GmbH, Frankfurt, Germany, by supplying botulinum toxin and providing a restricted grant to compen-sate for additional work such as detailed documentation and descriptive and comparative statistical analyses. Dr. Fietzek and Dr. Ceballos-Baumann have received honorariums for speeches from Merz Pharmaceuticals and from other compa-nies that manufacture botulinum toxin.
References
1. von Coelln R, Raible A, Gasser T, Asmus F. Ultrasound-guided injection of the iliopsoas muscle with botulinum toxin in campto-cormia. Mov Disord 2008;23:889–892.
2. Colosimo C, Salvatori FM. Injection of the iliopsoas muscle with botulinum toxin in camptocormia. Mov Disord 2009;24:316–317. Potential conflict of interest: Merz Pharmaceutical GmbH,
Frank-furt, Germany did not design the work, nor collect, analyze or inter-pret data, nor write any part of this report.
Published online 30 July 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22676
TABLE 1. linical characteristics and goal attainment T-scores for the two treatment groups
Treatment groups Iliopsoas N5 5 Rectus abdominis N5 5 Student’s t-test Mean6 SD Mean 6 SD Characteristics before treatment
Age (yr) 70.06 4.5 75.4 6 1.6 n.s.
Duration of camptocormia (yr) 1.96 0.2 3.06 1.4 n.s.
UPDRS part III 18.06 5.4 11.0 6 6.8 n.s.
Timed Up&Go 10 m (s) 9.76 6.3 9.16 2.4 n.s. Dosage (Units Xeomin) 2206 40 2006 63 n.s.
Injection sites 4–6 6–8
Goal attainment—T-scores
T-Score patient 29.86 3.6 27.2 6 7.1 n.s.
T-Score physician 33.76 6.3 29.0 6 7.9 n.s. n.s., not significant.
3. Ashour R, Jankovic J. Joint and skeletal deformities in Parkin-son’s disease, multiple system atrophy, and progressive supranu-clear palsy. Mov Disord 2006;21:1856–1863.
4. Wunderlich S, Csoti I, Reiners K, et al. Camptocormia in Parkin-son’s disease mimicked by focal myositis of the paraspinal muscles. Mov Disord 2002;17:598–600.
5. Holler I, Dirnberger G, Pirker W, Auff E, Gerschlager W. Camp-tocormia in idiopathic Parkinson’s disease: [(123)I]beta-CIT SPECT and clinical characteristics. Eur Neurol 2003;50:118–120. 6. Azher SN, Jankovic J. Camptocormia: pathogenesis, classification,
and response to therapy. Neurology 2005;65:355–359.
7. Cardillo JE, Choate RO, Kiresuk TJ, et al. Goal attainment scal-ing: applications, theory, and measurement, First ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1994.
Pregabalin- and Gabapentin-Associated
Myoclonus in a Patient with Chronic
Renal Failure
Video
We describe severe pregabalin-associated myoclonus and confusion in a patient with chronic renal failure. A similar reaction was observed when the patient was exposed to gaba-pentin, but not carbamazepine or amitriptyline.
Case History
A 47-year-old man presented with new-onset myoclonic jerking and confusion. He had chronic renal failure secondary to insulin-dependent diabetes mellitus and self-administered peritoneal dialysis four times daily. He was anuric, with a baseline urea and creatinine level of 22 mmol/L and 359 umol/L, respectively. Medications included insulin, alfa-calcidol, pravastatin, and nifedipine. Baseline neurological examination was normal, with the exception of distal loss of vibration sensation. In particular, there was no uraemia-asso-ciated movement disorders such as asterixis or myoclonus and the higher mention functions were normal.
Two days before developing neurological symptoms, the patient was commenced on pregabalin 75 mg bd for distal neuropathic pain. He became confused and drowsy, and he described visual hallucinations of small animals and people. He also developed generalized multifocal large amplitude myoclonic jerks that prevented ambulation. The jerks were spontaneous and exacerbated by voluntary action. A noise-provoked startle response habituated after repeated stimuli. There was no obvious myoclonus to touch.
The first video was taken 42 hours after stopping pregaba-lin (and four peritoneal dialysates). By this time the patient was able to walk and the video does not fully reflect the ini-tial severity of the myoclonus. The confusion and hallucina-tions had resolved and the myoclonic jerks were limited mainly to his upper limbs and shoulder.
Further improvement occurred, and 90 hours after stopping the drug (16 dialysates), the myoclonus had resolved and the patient felt back to normal. The second video was taken at this time, that is, 48 hours after the first video. Symptoms had resolved before neurophysiological testing could be arranged.
It is of interest that our patient had previously experienced similar reversible confusion and myoclonus on gabapentin 300 mg tds. Carbamazepine and amitriptyline, which proved ineffective for his pain, did not cause neurological side effects.
Discussion
The association between gabapentin and myoclonus is well characterized, probably as a result of longer and more ubiquitous use.1–3Huppertz et al. reported pregabalin-associ-ated focal myoclonus in four epileptic patients, and case reports of pregabalin-evoked status myoclonus have also been described.4,5 Recently, Hellwig and Amtage6 reported pregabalin-induced cortical negative myoclonus in a patient with mild renal impairment.
We present a case of reversible pregabalin-associated myo-clonus in a patient in whom gabapentin evoked the same reaction. Because pregabalin is excreted unchanged via the kidney, and assuming a similar pharmacokinetics to gabapen-tin (a highly hydrophilic compound with weak diffusion into adipose tissues), we speculate that excessive plasma accumu-lation lead to accumuaccumu-lation in cerebrospinal fluid and neuro-toxicity.7 This is supported by the complete resolution of symptoms after dialysis.
It is likely that the myoclonus was cortical in origin, based on its multifocal and action-induced nature and the superim-posed confusion and hallucination. However, the role of underling uraemia is unclear; for example, this may have lowered his myoclonus threshold.
Antiepileptic drugs that enhance inhibitory GABAergic neurotransmission (clonazepam, valproic acid, levetiracetam, and topiramate) do not cause myoclonus and are frequently used to treat it. In contrast, anticonvulsants that block neuro-nal excitation (carbamezapine, lamotrigine, gabapentin, and pregabalin) have little therapeutic role in myoclonus and can sometimes cause it. Despite the suggestion in their names, neither pregabalin nor gabapentin act via the inhibitory GABAergic system; evidence suggests that both drugs modu-late excitatory neurotransmittor release (glutamate, noradren-aline, and substance P) through the a-2 delta subunit of the voltage-gated calcium channel. This raises the possibility that this patient may harbor an undefined genetic risk variant such as a polymorphism in thea-2 delta subunit of the volt-age-gated calcium channel.
Video Legend
In the first segment, the patient is seen 42 hours after stop-ping pregabalin (and four dialysates) and, therefore, the video does not fully reflect the initial severity of his myoclonus. The patient is no longer confused, but there are multifocal action-induced myoclonic jerks, which are mainly distal. The second segment is 48 hours after the first video (90 hours and 16 dialysates after starting pregabalin) and shows com-plete resolution of symptoms.
Potential conflict of interest: None reported.
Published online 29 July 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22286
Daniel G. Healy* Department of Clinical Neurosciences Institute of Neurology University College London London, United Kingdom *E-mail: danhealy@doctors.org.uk Gordon T. Ingle NMR Research Unit, Institute of Neurology University College London London, United Kingdom Peter Brown Sobell Department of Motor Neuroscience and Movement Disorders Institute of Neurology London, United Kingdom
References
1. Asconape J, Diedrich A, DellaBadia J. Myoclonus associated with the use of gabapentin. Epilepsia 2000;41:479–481.
2. Zhang C, Darren G, Glenn DG, Bell WL, O’Donovan CA. Gaba-pentin-induced myoclonus in end-stage renal disease. Epilepsia 2005;46:156.
3. Gunal AI, Ozalp G, Yoldas TK, Gunal SY, Kirciman E, Celiker H. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 2004;19:3137–3139.
4. Huppertz HJ, Feuerstein TJ, Schulze-Bonhage A. Myoclonus in epilepsy patients with anticonvulsive add-on therapy with pregaba-lin. Epilepsia 2001;42:790–792.
5. Knake S, Klein KM, Hattemer K, et al. Pregabalin-induced gener-alized myoclonic status epilepticus in patients with chronic pain. Epilepsy Behav 2007;11:471–473.
6. Hellwig S, Amtage F. Pregabalin-induced cortical negative myo-clonus in a patient with neuropathic pain. Epilepsy Behav 2008; 13:418–420.
7. Blum RA, Comstock TJ, Sica DA, et al. Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther 1994;56:154 159.
Suicide Following Duodenal Levodopa Infusion
for Parkinson’s Disease
Depression is the most frequent psychiatric diagnosis in Parkinson’s disease (PD). However, the incidence of suicide is lower than or similar to the general population.1We report a patient with advanced PD who committed suicide 3 months after onset with duodenal levodopa infusion (Duodopa1), and discuss about possible implications.
A 38-year-old man presented with resting tremor in his right hand in 1980. On examination, there was an intermit-tent rest tremor, bradykinesia, and rigidity on his right side. He was diagnosed with PD. Initially he responded well to dopaminergic medication, but over time, he developed
increasing tremor, bradykinesia, rigidity, and gait difficulty. In 2006, at 64, his condition was deteriorated to advanced state (state 4 of Hoehn and Yahr scale). At that moment, he presented wearing off, sudden on-off, disabling dyskine-sias, gait freezing, and falling. Total UPDRS (Unified Parkinson’s Disease Rating Scale) scores during off state was 113 of 199 (UPDRS III was 65 of 108), whereas total UPDRS while on state was 68 of 199 (UPRS III was 34 of 108). MMSE (Mini Mental State Examination) was 25 of 30. He had been treated with sertraline (100 mg/day) and alprazolam (1 mg/day) since 2001 due to depressive symp-toms. Very occasionally he suffered from maniac ideas and was verbally aggressive with his wife. He did not meet cri-teria for deep brain stimulation (DBS) so he was put on subcutaneous apomorphine infusion. Although initially there was some motor improvement, he subsequently developed severe visual hallucinations and orthostatic hypotension. Apomorphine infusion was stopped. In May 2008, he started with duodenal levodopa infusion. An important decrease in motor fluctuations, off time, and dyskinesias was seen. Levodopa-equivalent dose was 1,572 mg/day. Evaluation 2 months after treatment onset showed a significant overall improvement. Suicidal ideation was not observed. He referred persistent depressive symptoms, anxiety, and insom-nia, presumably due to serious familiar problems (his daughter had been diagnosed with multiple sclerosis 2 years ago, and one of his grandsons had died a few months before beginning of Duodopa therapy). Trazodone was given in addition to sertraline. In August 2008, the patient was found hanged in his home bathroom.
DBS, dopamine agonist (apomorphine) infusion, and con-tinuous levodopa infusion are the three available options for advanced PD.2Gait disorder, poor improvement in on state, and cognitive and psychiatric symptoms made the patient unfit for DBS. After subcutaneous apomorphine infusion failed, Duodopa was considered as the last option for treat-ment. Although motor response was good, an unexpected consummated suicide occurred 3 months later.
Depression happens in approximately one third of patients with PD.3 However, suicidal ideation or attempts are uncommon in PD.1 In our case, the patient presented a chronic anxiety-depressive syndrome, hallucinations induced by apomorphine, and occasional minor psychotic behavior without dementia. Nevertheless, there was a good familiar and psychosocial support, and suicidal ideation or attempts before Duodopa therapy were not reported.
To our knowledge, this is the first case reported of suicide in a patient with PD on Duodopa. Suicide following DBS for PD has been previously described in several cases.4There is evidence to suggest a role for dopamine in the control of sui-cidal behavior. Indeed, it is known that reduced dopamine function in depressed patients is related to suicidal behav-ior,5 and a reduction in dopaminergic treatment may also play a part role in suicide following DBS. In our patient, although levodopa treatment could have been a theoretical protector factor for suicide, he committed suicide only 3 months after beginning with Duodopa. Maybe the suicidal ideation was already present, though not manifested, and the improvement in motor condition allowed the patient to commit suicide, previously impossible due to an extremely disabling situation. Hallucinations, confusion, nightmares, euphoria, psychotic episodes, and depression with very
Potential conflict of interest: Nothing to report.
Published online 30 July 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22708
uncommon suicidal ideation or attempts are reported in technical data of Duodopa. Increased impulsiveness was probably a major factor in suicidal behavior of some of patients after DBS. However, our patient had not suffered from impulse control disorders. Probably, motor ‘‘liber-ation’’ with effective treatment (be it DBS or Duodopa) and possibly increased impulsivity due to certain treatments may have prompted suicidal behavior. Although clinical charac-teristics in our patient were similar to those reported in pre-vious series,6suicide risk may have been underestimated. In fact, our patient had similar risk factors for suicidal and death ideation to a recently described series of patients with PD.7Whereas a single case report can not provide valid in-formation on overall suicide risk in patients treated with Duodopa, it is advisable to draw attention to the problem and encourage further research.
In conclusion, we report the first case of patient with PD who committed suicide following duodenal levodopa infusion therapy. Although continuous levodopa infusion is an effec-tive therapy in advanced PD, it is not exempt from severe complications, and also minor surgical is necessary. This case suggests the need to identify patients at risk of suicidal behavior before administering intraduodenal levodopa. We must be alert if other cases should happen.
Diego Santos-Garcı´a, MD, PhD* Mercedes Macı´as, MD Miguel Llaneza, MD A´ ngel Aneiros, MD Section of Neurology Hospital A. Marcide Ferrol, Spain *E-mail: diegosangar@yahoo.es References
1. Mainio A, karvonen K, Hakko H, Sa¨rkioja T, Ra¨sa¨nen P. Parkinson’s disease and suicide: a profile of suicide victims with Parkinson’s disease in a population-based study during the years 1988–2002 in Northern Finland. Int J Geriatr Psychiatry (in press).
2. Fahn S. How do you treat motor complications in Parkinson’s dis-ease: medicine, surgery, or both? Ann Neurol 2008;64;S56–S64. 3. Rojo A, Aguilar M, Garolera MT, Cubo E, Navas I, Quintana S.
Depression in Parkinson’s disease: clinical correlates and out-comes. Parkinsonism Relat Disord 2003;10:23–28.
4. Voon V, Krack P, Lang AE, et al. A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson’s dis-ease. Brain 2008;131:2720–2728.
5. Pitchot W, Hansenne M, Gonzalez Moreno A, et al. Reduced do-pamine function in depressed patients is related to suicidal behav-ior but not its lethality. Psychoneuroendocrinology 2001;26:689– 696.
6. Devos D;for the French DUODOPA Study Group. Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson’s disease. Mov Disord 2009;24:993–1000. 7. Nazem S, Siderowf AD, Duda JE, et al. Suicidal and death
idea-tion in Parkinson’s disease. Mov Disord 2008;23:1573–1579.
Motor–Phonic Tic Mimicking Essential
Palatal Myoclonus
Video
Tics commonly involve the oropharyngeal muscles produc-ing clickproduc-ing or other sounds. Although tics are classically brief and intermittent, unusual presentations with continuous, stereotypic, and rhythmic movements can be part of the spectrum of tic phenomenology.1 We describe 2 patients, a 21-year-old man (Patient 1) and a 12-year-old boy (Patient 2), with Tourette syndrome (TS), who presented with palatal tics (PT) resembling essential palatal myoclonus (EPM). The duration of their symptoms was 24 and 6 months, respec-tively. Both patients exhibited repetitive, rhythmic (50 cycles/minute) soft palate elevation movements, accompanied by a synchronous clicking sound (Supporting Information Video Segments 1 and 2), which is partially suppressible and distractible, present with the mouth both closed and open. The movements were continuous during our examination; however, both patients reported daily periods of remission lasting several minutes to hours. The movements were reported as being absent during sleep (Patient 1). Both patients denied premonitory sensations. Other tics included knuckle popping, lower lip sucking and licking (Patient 1), and hand clapping, head hitting, neck extension, blinking, grimacing, and other complex motor tics (Patient 2). Both patients had associated neuropsychiatric comorbidities (obses-sive compul(obses-sive behavior [OCB], attention deficit disorder [ADD], and impulsivity). Patient 1 reported a family history of tics (father and brother), trichotillomania (father, paternal uncle), and ADD (two maternal cousins). Patient 2 also had a family history of ADD (father) and OCB (mother). Both patients had a normal neurological examination, except for tics and ADD, and normal brain imaging. The frequency and amplitude of palatal movements improved markedly on treatment with fluphenazine (Patient 1) and tetrabenazine (Patient 2).
The 2 patients with PT manifested motor and phonic tics consistent with TS; in one case, the palatal movements were erroneously attributed to another movement disorder, namely EPM.
EPM is characterized by rhythmic and continuous contrac-tions of the tensor veli palatini muscle, which opens the eustachian tube and causes an abrupt decrease in the surface tension within the tube, thus creating a clicking sound.2 Because the movement consists of brief, rhythmical contrac-tions of a single muscle rather than an oscillatory movement produced by opposing antagonist muscles, we prefer the term myoclonus rather than tremor. The etiology of EPM is unknown; its designation as ‘‘essential’’ serves to distinguish it from symptomatic palatal myoclonus (SPM), which is asso-ciated with other neurological deficits, often following brain-stem lesions affecting the triangle of Mollaret.3
Additional Supporting Information may be found in the online version of this article.
Potential conflict of interest: None reported.
Published online 11 August 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22733
The differential diagnosis of isolated palatal myoclonus also includes psychogenic palatal myoclonus (PPM).4,5 PPM is distinguished by the presence of a premovement potential (Bereitschaftspotential), suggesting that PPM is generated through mechanisms common to those underlying self-initi-ated, voluntary movements.4Rarely, individuals with unusual control of the pharyngeal muscles can voluntarily produce rhythmical palatal movements. This special skill can be acquired6or inherited.7
In contrast to typical EPM or SPM, the palatal move-ments in our patients had a lower and variable frequency, were distractible, remitted intermittently, and appeared to
involve more widespread oropharyngeal muscle groups. In addition, the presence of ear clicking, normal brain imaging, and the absence of other neurological deficits excluded SPM. Even though temporarily suppressible, the palatal movements were perceived by our patients as involuntary, making the diagnosis of volitional/special skill palatal myo-clonus unlikely. In contrast to PPM, which may be more difficult to differentiate, the palatal movements in the cases described persisted with the mouth both closed and open, were not entrainable, and lacked other supportive features of a psychogenic etiology (Table 1). The presence of other motor or phonic tics and the coexistence of behavioral TABLE 1. Clinical features distinguishing different forms of palatal myoclonus
EPM2 SPM3 PT1 PPM4,5 Volitional6,7
Type Involuntarya Involuntary Involuntary/
Semivoluntary
Perceived as involuntary
Voluntary Frequency Rhythmic, continuous
1256 70 cycles/min Rhythmic, continuous 1396 51 cycles/min Rhythmic, more irregular, 40–50 cycles/min with intermittent remissions Variable frequency, fluctuating, 60–120 cycles/min Variable frequency, under volitional control, up to 150 cycles/min Muscles involved Tensor veli palatini
(cranial nerve V)
Levator veli palatini (cranial nerve IX, X)
Usually other oropharyngeal muscles; tensor and levator veli palatine—possibleb
Usually other oropharyngeal muscles; tensor veli palatine—possible
Tensor and levator veli palatini
Ear clicking Almost always Rarely Yes Variable (the
movements usually cease during speaking) Yes Suppressibility by voluntary control
Rarely No Yes, temporarily Yes, temporarily Yes
Suppressibilty by sensory trick
Possible No No Possiblec N/A
Presence during sleep
Absent Present Absentd Absentd N/A
Presence with mouth open
Persists Persists Persists Variable Variable
Mental activation Usually resistant Highly resistant Variable Distractible Resistant
Entrainment Absent Absent Absent Present Absent
Premonitory sensory phenomena
Absent Absent Usually present Possible Absent
Other features N/A Ataxia Dysarthria
Nystagmus Contraction of oropharynx, larynx, esophagus, diaphragm
Other motor and phonic tics Associated behavioral comorbidities. Responsive to verbal suggestion Onset usually acute3 Responds to placebo treatment3Associated psychopathology Previous exposure to cases of organic myoclonus (modeling) May be asymmetric
Neuroimaging Normal Olivary
pseudohypertrophy
Normal Normal Normal
a
The cases of EPM with voluntary control6,7are classified as volitional/special skill palatal myoclonus. bNo electrophysiology data available.
c
Sensory tricks have been previously described in psychogenic movement disorders. d
symptoms (e.g., OCB, ADD) are essential in making the correct diagnosis of PT.
The distinction of PT from EPM and other palatal movement disorders is important not only because the prognosis and potential neurological comorbidities vary but also because the treatment differs. Antidopaminergic drugs are often effective in the treatment of multifocal tics, which was the case in our 2 patients. Behavioral comorbid-ities in patients with TS need to be addressed and treated, as they can be just as disabling as the motor symptoms. Botulinum toxin injections may be considered as a thera-peutic option in focal movement disorders, including EPM and PT.
Legends to the Video
Segment 1. Neurological examination in Patient 1 demon-strating relatively rhythmic palatal movements accompanied by clicking noise.
Segment 2. Neurological examination in Patient 2 demonstrating relatively rhythmic palatal elevations accompanied by more widespread oropharyngeal muscle movements.
Octavian R. Adam, MD Joseph M. Ferrara, MD Joseph Jankovic, MD* Department of Neurology Parkinson’s Disease Center and Movement Disorders Clinic Baylor College of Medicine Houston, Texas *E-mail: josephj@bcm.tmc.edu
References
1. Schwingenschuh P, Wenzel K, Katschnig P, Saurugg R, Ott E. Case of palatal tic resembling palatal tremor in a patient with Tourette syndrome. Mov Disord 2007;22:742–745.
2. Deuschl G, Wilms H. Clinical spectrum and physiology of palatal tremor. Mov Disord 2002;18 (Suppl 2):S63–S66.
3. Zadikoff C, Lang A, Klein C. The ‘‘essential’’ of essential palatal tremor: a reappraisal of the nosology. Brain 2006;129:832–840. 4. Pirio Richardson S, Mari Z, Matsuhashi M, Hallett M.
Psycho-genic palatal tremor. Mov Disord 2006;21:274–276.
5. Williams D. Psychogenic palatal tremor. Mov Disord 2004;19: 333–335.
6. Seidman M, Arenberg J, Shirwany N. Palatal myoclonus as a cause of objective tinnitus: a report of six cases and a review of the literature. Ear Nose Throat J 1999;78:292–294.
7. Klein C, Gehrking E, Vieregge P. Voluntary palatal tremor in two siblings. Mov Disord 1998;13:545–548.
