Recent eLetters

I would like to commend the authors on this informative review on the utility of dopamine transporter SPECT in the diagnostic workup of Parkinsonian syndromes. I acknowledge that this review is set in the context of the labelled indications for DaTSCAN as outlined by the EMA and FDA however from a pragmatic perspective I would like to highlight the utility of dopamine transporter SPECT in differentiating drug-induced Parkinsonism from Idiopathic Parkinson's disease (or other neurodegenerative Parkinsonian syndromes) where diagnostic uncertainty exists. Phenomenology can be unrewarding when trying to differentiate drug-induced Parkinsonism, a common cause of Parkinsonism in the elderly, from Idiopathic Parkinson's disease. The presence of normal dopamine transporter SPECT imaging can be reassuring for both the clinician and the patient when confirming a drug-induced aetiology (1). An important caveat however is that dopamine antagonists and related agents can unmask incipient Parkinson's disease thus regular examination and followup remain perhaps the most important tools in the investigation of Parkinsonism.

Reference:

1. Cummings JL, Henchcliffe C, Schaier S et al. The role of dopaminergic imaging in patients with symptoms of dopaminergic system neurodegeneration. Brain 2011: 134; 3146-3166.

Conflict of Interest:

None declared

Introduction- We read the article written by Garcin et al. (4) about transcranial magnetic stimulation (TMS) as an efficient treatment for psychogenic movement disorders (PMD) with great interest. The authors report the efficacy of TMS on 24 adult patients with chronic PMD. Twenty low frequency stimuli were delivered over the motor cortex with a circular coil. The authors observed an immediate significant improvement in 75% of patients treated with complete resolution in a third of these patients. We would like to relate our similar experience with TMS for patients with PMD.

Patients and methods- We retrospectively reviewed the medical records of 19 patients (14 females, 5 males) with PMD who received TMS in Rouen University Hospital's Neurophysiology Department between January 2004 and September 2010. Average age was 29.7 +- 15.3 years (mean +- SD, min-max: 8-61 years). Symptoms were tremor (n=10), myoclonia (n=5), or dystonia (n=4). Movement disorders affected either one upper limb (n=10), one lower limb (n=3), both upper limbs (n=1), both lower limbs (n=2), the face (n=2), or hemibody (n=1). Median symptom duration at the time of consultation was 21 days (min-max: 1-2000). Symptoms were acute (<30 days) in 12 patients, subacute (between 30 days and 6 months) in 3 patients, or chronic (>6 months) in 4 patients. Thirty stimuli were delivered over the motor cortex (contralaterally to symptoms or bilaterally in case of bilateral movement disorders), with a circular coil at low frequency (0.2 Hz) with a maximum intensity of 2.5 Tesla. If symptoms persisted 2 days after the first treatment (n=3), a second stimulation session was carried out between the 2nd and 7th days using the same parameters. The diagnosis of PMD which presents as a neurologic disease but without any organic damage to the nervous system was explained to each patient. TMS efficacy was classified in two groups according to subjective evaluations realized by both the patient and the neurologist: Patients were classified in the "effective" group if recovery was complete or if the patient presented a dramatic improvement and in the "ineffective" group if mild or no improvement was observed. The local ethics committee approved this retrospective study.

Results- TMS was effective in 95% of the 19 patients with PMD. A complete recovery was observed in 15 patients (79%). Ten patients recovered immediately after TMS, 2 patients recovered almost immediately after TMS (within a few minutes or hours, but less than 24 hours), and 3 patients recovered after the second TMS session. TMS was ineffective in 1 patient, a 49-year-old woman with a right-hand tremor that had appeared after an armed robbery three years earlier. No side effects were noted. The initial symptoms recurred in 4 patients: One patient experienced a single recurrence of her PMD one month after treatment. Three patients had multiple recurrences between one month and one year after treatment. TMS was once again used to treat these recurrences and was immediatly and entirely effective for all recurrences. At least one precipitating event was identified in 12 patients. Nine patients described precipitating events that were psychosocial in nature (work-related stress, personal conflict, the death of family member). A physically traumatic event in the affected limb occured in 4 patients, and, in 2 of these patients, the injury was considered particularly minor. No precipitating event was found in 7 patients. Seven patients had psychiatric comorbidities such as anxiety and depressive disorders.

Discussion- We find TMS to be effective in treating PMD, confirming the results of Garcin et al. (4). We observed a much higher response rate among our patients, but this was to be expected as very few chronic patients were included (4 patients) in our study. In the study of Garcin et al., the population was composed solely of chronic patients who are thought to be more difficult to treat. Treatment is less effective the later it is implemented, suggesting that PMD should be diagnosed and treated as quickly as possible (5). Dafotakis et al. found that tremor decreased in 11 patients with psychogenic tremor after one TMS session with similar parameters, but Dafotakis et al. used a figure-eight coil for their protocol (3). The two techniques differ in terms of the stimulated cortical volume. (A circular coil stimulates a larger cortical volume than a figure-eight coil.) The TMS procedure used in our protocol (the same as that of Garcin et al.(4)) has proven to be safe in other psychogenic disorders (1,2). Our TMS procedure is widely available since even modest neurophysiology departments have a circular coil on hand that is used for motor evoked potentials. The efficacy mechanisms of TMS stimulation are unknown. One possible explanation is that TMS stimulation modifies cortical excitability or connectivity. A small number of stimuli applied with a figure-eight coil are known to not modify cortical excitability, but the studies that illustrate this lake of modification were not done with a circular coil. In addition, a placebo effect cannot be ruled out. A multicentric randomized controlled trial versus placebo is ongoing (NCT01352910) to measure the importance of the placebo effect.

Conclusion- A majority of patients with PMD recover following transcranial magnetic stimulation suggesting that TMS should be used in PMD.

Conflict of Interest:

None declared

Introduction- We read the article written by Garcin et al. (4) about transcranial magnetic stimulation (TMS) as an efficient treatment for psychogenic movement disorders (PMD) with great interest. The authors report the efficacy of TMS on 24 adult patients with chronic PMD. Twenty low frequency stimuli were delivered over the motor cortex with a circular coil. The authors observed an immediate significant improvement in 75% of patients treated with complete resolution in a third of these patients. We would like to relate our similar experience with TMS for patients with PMD.

Patients and methods- We retrospectively reviewed the medical records of 19 patients (14 females, 5 males) with PMD who received TMS in Rouen University Hospital's Neurophysiology Department between January 2004 and September 2010. Average age was 29.7 +- 15.3 years (mean +- SD, min-max: 8-61 years). Symptoms were tremor (n=10), myoclonia (n=5), or dystonia (n=4). Movement disorders affected either one upper limb (n=10), one lower limb (n=3), both upper limbs (n=1), both lower limbs (n=2), the face (n=2), or hemibody (n=1). Median symptom duration at the time of consultation was 21 days (min-max: 1-2000). Symptoms were acute (<30 days) in 12 patients, subacute (between 30 days and 6 months) in 3 patients, or chronic (>6 months) in 4 patients. Thirty stimuli were delivered over the motor cortex (contralaterally to symptoms or bilaterally in case of bilateral movement disorders), with a circular coil at low frequency (0.2 Hz) with a maximum intensity of 2.5 Tesla. If symptoms persisted 2 days after the first treatment (n=3), a second stimulation session was carried out between the 2nd and 7th days using the same parameters. The diagnosis of PMD which presents as a neurologic disease but without any organic damage to the nervous system was explained to each patient. TMS efficacy was classified in two groups according to subjective evaluations realized by both the patient and the neurologist: Patients were classified in the "effective" group if recovery was complete or if the patient presented a dramatic improvement and in the "ineffective" group if mild or no improvement was observed. The local ethics committee approved this retrospective study.

Results- TMS was effective in 95% of the 19 patients with PMD. A complete recovery was observed in 15 patients (79%). Ten patients recovered immediately after TMS, 2 patients recovered almost immediately after TMS (within a few minutes or hours, but less than 24 hours), and 3 patients recovered after the second TMS session. TMS was ineffective in 1 patient, a 49-year-old woman with a right-hand tremor that had appeared after an armed robbery three years earlier. No side effects were noted. The initial symptoms recurred in 4 patients: One patient experienced a single recurrence of her PMD one month after treatment. Three patients had multiple recurrences between one month and one year after treatment. TMS was once again used to treat these recurrences and was immediatly and entirely effective for all recurrences. At least one precipitating event was identified in 12 patients. Nine patients described precipitating events that were psychosocial in nature (work-related stress, personal conflict, the death of family member). A physically traumatic event in the affected limb occured in 4 patients, and, in 2 of these patients, the injury was considered particularly minor. No precipitating event was found in 7 patients. Seven patients had psychiatric comorbidities such as anxiety and depressive disorders.

Discussion- We find TMS to be effective in treating PMD, confirming the results of Garcin et al. (4). We observed a much higher response rate among our patients, but this was to be expected as very few chronic patients were included (4 patients) in our study. In the study of Garcin et al., the population was composed solely of chronic patients who are thought to be more difficult to treat. Treatment is less effective the later it is implemented, suggesting that PMD should be diagnosed and treated as quickly as possible (5). Dafotakis et al. found that tremor decreased in 11 patients with psychogenic tremor after one TMS session with similar parameters, but Dafotakis et al. used a figure-eight coil for their protocol (3). The two techniques differ in terms of the stimulated cortical volume. (A circular coil stimulates a larger cortical volume than a figure-eight coil.) The TMS procedure used in our protocol (the same as that of Garcin et al.(4)) has proven to be safe in other psychogenic disorders (1,2). Our TMS procedure is widely available since even modest neurophysiology departments have a circular coil on hand that is used for motor evoked potentials. The efficacy mechanisms of TMS stimulation are unknown. One possible explanation is that TMS stimulation modifies cortical excitability or connectivity. A small number of stimuli applied with a figure-eight coil are known to not modify cortical excitability, but the studies that illustrate this lake of modification were not done with a circular coil. In addition, a placebo effect cannot be ruled out. A multicentric randomized controlled trial versus placebo is ongoing (NCT01352910) to measure the importance of the placebo effect.

Conclusion- A majority of patients with PMD recover following transcranial magnetic stimulation suggesting that TMS should be used in PMD.

References-

1. Chastan N, Parain D: Psychogenic paralysis and recovery after motor cortex transcranial magnetic stimulation. Mov Disord 25:1501-1504, 2010 2. Chastan N, Parain D, Verin E, et al: Psychogenic aphonia: spectacular recovery after motor cortex transcranial magnetic stimulation. J Neurol Neurosurg Psychiatry 80:94, 2009 3. Dafotakis M, Ameli M, Vitinius F, et al: [Transcranial magnetic stimulation for psychogenic tremor - a pilot study]. Fortschr Neurol Psychiatr 79:226-233, 2011 4. Garcin B, Roze E, Mesrati F, et al: Transcranial magnetic stimulation as an efficient treatment for psychogenic movement disorders. J Neurol Neurosurg Psychiatry 5. Gupta A, Lang AE: Psychogenic movement disorders. Curr Opin Neurol 22:430-436, 2009

Conflict of Interest:

None declared

We thank Dr. Juan A Simal-Julian and collaborators (1) for their interest in our paper (2). We also appreciate the commentaries of Drs. Oldfield and Jane jr (3), Laws (4) and Warnke (5).

We will first address the letter of Dr. Simal-Julian and then will offer a few words on the commentaries of Drs. Oldfield and Jane jr, Laws and Warnke.

Mortini et al (6) use the microscope to remove the adenoma via a sub labial trans-septal avenue. This is the classic microscopic approach for the removal of pituitary adenoma. The word endoscope does not appear in the key words and, in a 12 page long paper containing more than 6,000 words, is mentioned only once in the following paragraph "After the removal of large macro adenomas and completion of hemostasis, the inspection of the intrasellar space is carried out using rigid endoscop 4-mm in diameter with 0- and 30- degree lenses (Karl Storz, Tuttlingen, Germany)" (6). We really do not think that the Mortini's paper may be accurately characterized as endoscopic assisted. The readers may make their own judgment. Regarding vascular complications we included "...carotid or other vessels injury, intracerebral hematoma, or any symptomatic intratumoral or intrasellar hemorrhage. Venous bleeding from the cavernous sinus was tabulated as a vascular complication (only) when it prevented the completion of the surgical procedure. Epistaxis was not included among the vascular complications" (2). We feel that this is a reasonable list of vascular complications. Spheno-palatine artery injury, contrary to what our colleagues state, was not tabulated as vascular complication even when it required treatment be it cauterization or packing, because we recognized that this is often, but not always, a minor complication. Again the readers may make their own judgment. We looked at the relationship between the tumor size in the endoscopic or microscopic group and the vascular injury rate and we commented on that "Furthermore the macro tumors or the extent of complete tumor resection, 2 variables that could have affected the vascular complication rate, were found to be not statistically significant in the endoscopic or microscopic series reporting vascular complications (p=0.24 and 0.10 for macro tumor size and complete resection respectively)"(2) The methodology we used was the same used by Tabaee et al (7)in a widely quoted paper on endoscopic pituitary surgery "Tabaee et al have used this methodological approach in 2009 when reviewing endoscopic pituitary surgery." (2)

We agree with Drs. Oldfield and Jane (3) that there might be indications where one or the other technique has superior results, everything else being equal; we also agree with their statement that we should identify these indications. As we said in our paper ,quoting a source8 that has nothing to do with endoscopic/microscopic pituitary surgery, the majority of surgical innovations are incremental and are " ...prone to overoptimistic assessments by their developers and ,therefore, need controlled randomized studies, when possible" (2). We disagree with Dr. Laws (4) that we denigrate endoscopic pituitary surgery; on the contrary by trying to define what is that new technologies/new processes bring to the fore we make them , in the long term, more sustainable. Indeed we use endoscopy to deal with extradural cranial base lesions and often inspect the resection cavity with endoscopes after microsurgical removal of pituitary adenomas. It is conceivable that in the medium term we, doctors and health care organizations, will be reimbursed for the use of new technology/processes only when the advantages associated with them are clearly evident and measurable. So we agree with Dr. Warnke (5) that " ...if we want to establish new techniques and get funding for its use: sound randomized controlled trials with appropriate primary and secondary outcome measures" (5) are sorely needed. In summary, our paper is not pro or against anything but serves, we hope, to remind us that we need to get better at how we introduce new technology/processes, especially when any improvement might be at the margins. We wish more attention would have been paid to the perspective section of our contribution. The general concept of how we introduce surgical innovations is, in our opinion, a progressive concept , not a regressive or a naysayer posture and it is extremely relevant to the whole field of surgery/neurosurgery.

References 1. Simal-Julian JA, Miranda-Lloret P, Perez-Borreda P et al: Microscopy versus endoscopy in pituitary surgery. J Neurol Neurosurg Psychiatry. Published Online First:January 18-2013 2. Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and metaanalysis.?J Neurol Neurosurg Psychiatry. Published Online First: 15 December 2012 doi:10.1136/jnnp-2012-303194 3. Oldfield EH, Jane JA Jr: Endoscopic versus microscopic pituitary surgery. J Neurol Neurosurg Psychiatry. Published Online First: 23 January 2013 doi:10.1136/ jnnp-2012-304583 4. Laws ER. Complications of transsphenoidal surgery: the shortcomings of meta-analysis. J Neurol Neurosurg Psychiatry. Published Online First: 16 February 2013 doi:10.1136/jnnp-2012-304541 5. Warnke P: Case series analysis, meta-analysis or no analysis in the evaluation of neurosurgical techniques: get better or get out J Neurol Neurosurg Psychiatry. Published Online First: March 5, 2013 doi:10.1136/ jnnp-2013-305130 6. Mortini P, Losa M, Barzaghi R et al. Results of transsphenoidal surgery in a large series of patients with pituitary adenoma. Neurosurgery 2005; 56:1222-33 7. Tabaee A, Anand VK, Barron Y, et al. Endoscopic pituitary surgery: a systematic review and meta-analysis. J Neurosurg 2009;111:545-54 8. McCulloch P, Altman DG, Campbell WB et al No surgical innovation without evaluation: the IDEAL recommendations. Lancet 2009;374:1105-12

Conflict of Interest:

None declared

Sir, The paper by Rosenow et al1 made interesting reading. However, there are few concerns with respect to the conclusions of the study. The study tested for superiority of levetiratecam over lamotrigine with seizure free interval in the first 6 weeks of the trial as the primary endpoint. Assuming a clinically relevant difference of 15% between the groups, the authors estimated a sample size of 183 patients to achieve power of 80%. With a 10% drop-out estimate, the total sample size calculated was 203 patients. The study documents 165 protocol violations, 116 in levtiracetam group (56.3%) and 129 in lamotrigine group ( 63%). The authors, however, do not describe the nature of protocol violations. Given the fact of more than 50% protocol violations, one need to be skeptical about the ability of the trial to demonstrate any valid results on either direction ( either to demonstrate that the null hypothesis is indeed true- that levtiracetam is not significantly different from lamotrigine- or that it is rejected). Here, it would have been interesting if the authors reflected on the power of the study with 50% of the sample lost due to protocol violation. According to the authors the target daily dose of levetiracetam was achieved by 3 weeks and that of lamotrigine by 7 weeks. In such a situation, one wonders at the prudence of considering seizure free interval at the 6 weeks as the primary end point ( when the comparator agent has not even reached its target dose). This would makes the trial design skewed in favour of levtireacetam. The fact that it still didn't detect a difference between the two drugs could be because of three reasons: 1) Gross underpowering of the study because of protocol violation that it is no longer able to detect any significant change even if there was any 2) Absence of any appreciable difference between the drugs even with a skewed baseline disposition between the two drugs, 3) Absence of sufficient event rates within the 6 weeks period that make such a short term end point inappropriate to compare the efficacy of the drugs studied. The latter scenario is particularly relevant because there are about 20% of patients with 'first seizure' enrolled in the trial. It will be interesting to know about the natural seizure recurrence rate in that subgroup of patients. In the study, however, this cannot be verified because we do not ( and cannot) have a placebo arm. The authors' statement that the fact of identical ITT and PP analyses results indicate that protocol violations have no influence in the results of the primary analysis does not follow the dictum of a most plausible and direct explanation. Rather, it is the above-mentioned issues (especially the underpowering of the study and uncertain event rates in untreated patients) that could most plausibly make the ITT and PP analyses give identical results. Again, with such gross underpowering of the study, the lengthy discussion on 'subgroup' analysis appears without much statistical grounds. In the discussion section, the authors make further claims that is unfounded by the design and the results of the study. For the sake of brevity, I shall list few of them 1) "It is possible that side effects would be less prominent if extended release formulations were used" 2) " More rapid titration does not necessarily translate into a clinically relevant reduction in the rate of early recurrence, especially when considering monotherapy in a population with a relatively low risk of recurrence". 3) The final discussion on the prudence of including patients with single seizure and high risk of recurrence in the discussion section do not bear any relevance with the overall results of the study In conclusion, the study do not prove or disapprove that levetiracetam is better than lamotrigine for the specified end points. What appear unclear here are the reasons that makes a short term study of 26-weeks giving protocol violation to the tune of 50%, especially in a condition like epilepsy where patients are generally motivated to be on long term therapy. It will be interesting if authors can clarify on the reasons and nature of 'protocol violations'. Reference 1. Rosenow F, Schade-Brittinger C, Burchardi N, Bauer S, Klein KM, Weber Y, et al. The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy--an open-label, prospective, randomised controlled multicenter study. J Neurol Neurosurg Psychiatry. 2012 Nov;83(11):1093-8.

Conflict of Interest:

None declared