I read with interest O'Sullivan et al. short report on psychogenic non-epileptic seizures (PNES) and how to improve their recognition among physicians not skilled in neurosciences. 1The authors found that diagnostic accuracy and clinical confidence improved after a 15 minute teaching presentation on PNES and epileptic seizures (ES). It is said that the eye cannot see what the mind does not know. One cannot confidently diagnose PNES clinically if one is unaware of the clinical semiology which is thought to be incompatible with ES (side to side shaking movements of the head, pelvic thrusting and so forth). Increased knowledge of the same shall certainly improve the diagnostic accuracy and clinical confidence to diagnose PNES especially among non-neurologists. Trained epileptologists like me face another challenge and that is of too much knowledge which at times can be detrimental. We sometimes tend to over think our decisions- looks like a PNES clinically, has no surface EEG correlate but can it still be a weird frontal lobe seizure? Am I missing something? Maybe I should not stop the anticonvulsant after all. When it comes to PNES, it seems there is no perfect answer and hence these patients are often misdiagnosed for years.

Reference

1. O'Sullivan SS, Redwood RI, Hunt D, McMahon EM, O'Sullivan S. Recognition of psychogenic non-epileptic seizures: a curable neurophobia? J Neurol Neurosurg Psychiatry. 2013; 84:228-31.

Conflict of Interest:

None declared

With interest, we read an excellent paper written by a German group, in which four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) carried IgG autoantibodies against contactin-1 (CNTN1) expressed at the paranodes in the peripheral nerves.[1] Human IgG antibodies consist of four subclasses (IgG1-4) with different structural and functional characteristics. IgG4 are generally believed to be non- inflammatory antibodies because they poorly bind to complement and Fc receptors Three of their patients had anti-CNTN1 IgG4 and sera from these three patients bound the paranodes in the mouse teased nerve fibers. On the other hand, the remaining patient with no anti-CNTN1 IgG4 antibodies in the serum did not bind the paranodes.

In a large cohort of Japanese patients with CIDP (n = 533) and Guillain-Barre syndrome (GBS) (n = 200), our group identified anti-CNTN1 IgG antibodies in 16 sera from patients with CIDP and five with GBS.[2] IgG4 antibodies to CNTN1 were identified in 13 of 16 patients with CIDP, but none of those with GBS. IgG2 antibodies to CNTN1 were identified in three patients with CIDP and in five patients with GBS. We also blindly tested the sera on mouse teased fibers. Of interest, all the IgG4-positive CIDP sera strongly reacted against the paranodal domains but not for the IgG2-positive sera from patients with CIDP or GBS. These results are in line with those of the German group,[1] suggesting that only the IgG4 antibodies are pathogenic.

We further tested whether these sera activate the complement pathway in vitro.[2] None of the sera with anti-CNTN1 IgG4 antibodies induced the deposition of activated C3 components on enzyme-linked immunosorbent assay plates. These results support that anti-CNTN1 IgG4 antibodies do not fix complement.

The German group found out a typical clinical picture among the CIDP patients with anti-CNTN1 antibodies, namely acute onset of disease and severe motor symptoms, with three out of four patients manifesting action tremor.[1] However, in our cohort we found out that presence of anti-CNTN1 IgG4 antibodies was significantly associated with the clinical sign of sensory ataxia.[2] CNTN1 was widely expressed in large dorsal root ganglion neurons. Similarly, CIDP sera with anti-CNTN1 IgG4 antibodies stained large neurons in dorsal root ganglion sections and co-localized with CNTN1 staining in the soma and at the paranodes of sensory axons. These results support that the anti-CNTN1 autoantibodies induce the development of sensory ataxia. Nonetheless, the clinical feature of our patients contrasted with previous studies where none of the three German patients and only one of four Spanish patients with anti-CNTN1 IgG4 antibodies showed sensory ataxia.[1,3] The reason for this discrepancy is unclear, but this discrepancy should motivate international study groups to investigate the clinical feature of the anti-CNTN1 IgG4 antibodies among different countries, and their underlying mechanism.

References 1. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 2015 Feb 18. pii:jnnp-2014- 309916. doi: 10.1136/jnnp-2014-309916. 2. Miura Y, Devaux N, Fukami Y, et al. Contactin 1 IgG4 associated to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015 Mar 25. pii: awv054. 3. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013;73:370-80.

Conflict of Interest:

None declared

We would like to share several observations that we made on Ammirati et al. recently published meta-analysis. The authors reviewed the available English-language literature from 1990 to the present, comparing microsurgery versus endoscopy for treatment of pituitary adenomas, and conducted a systematic review and meta-analysis of the data obtained. The authors concluded that the two treatment methods produced similar outcomes for all of the variables analyzed, except for a statistically significant higher rate of vascular complications with endoscopy. We want to point out that endoscopy-assisted studies were included in the microsurgery cohort, including most notably a study by Mortini et al.1 involving 1140 patients, which represented 32.4% of all of the microsurgery cases and thus was weighted heavily in the analysis. The use of intraoperative endoscopy after microscopic resection provides the advantages of endoscopic procedures, such as better visualization of structures and of lateral and suprasellar limits, as well as differentiation between normal and diseased tissue. Inclusion of these patients introduces significant bias, strongly favoring microsurgery by giving it the advantages of endoscopy, and complicating a comparison between the two methods. Additionally, the variety of complications that were grouped together as vascular complications was highly heterogeneous, encompassing carotid lesions, lesions in less important vessels like the sphenopalatine artery, intracranial or sellar hemorrhages, ischemic infarcts, and cavernous sinus bleeding. While all of these complications are of a vascular nature, their characteristics and the resulting morbidity/mortality can be quite different. The limitations of microsurgery for treatment of significant invasions into the cavernous sinus are well known. Thus, when approaching an invasive cavernous sinus adenoma endoscopically for treatment, as in the study by Zhang et al.2, consideration of vascular complications from cavernous sinus bleeding is not comparable to microsurgical approach cases where there was no initial intention to treat invasive cavernous sinus tumors. Moreover, based on available data, we can only be certain that 57,6% (2027/3518) of the microscopic patients were macroadenomas, whereas 77% (1453/1887) of the cases were macroadenomas in the endoscopic cohort. This heterogeneous distribution of patients for something as fundamental as differentiation between micro and macroadenomas could have influenced the meta-analysis results, especially the observed rates of complete resection, vascular complications and csf leak. It is also worth noting that of the 22 microsurgery studies included, only 12 had data on vascular complications, whereas 17/24 endoscopic studies had such data. Meta- analysis variable data are collected more frequently, in general, in endoscopic studies than in microsurgery studies.As for the meta-analysis methodology, depending on the heterogeneity between studies, fixed effect models or randomized models were applied. Randomized models provide more conservative estimates than fixed effect models, and therefore are more apt to miss existing differences. These methods were used to compare rates of diabetes insipidus, hypopituitarism, and complete resection. All trended toward favoring the endoscopy group, but without statistical significance. Death rates for the microsurgery and endoscopy cohorts were 0.23% and 0.49%, csf leak 6.34 vs 7%, meningitis 2,08 vs 1.11%, vascular complication 0.5 vs 1.58%, visual loss 0.60 vs 0.72%, diabetes insipidus temporary 10.23 vs 9.10% and permanent 4.25 vs 2.31%, hypopituitarism 11,64 vs 8.51%, nerve injury 0.53 vs 0.28% and complete resection 64.44 vs 68.77% respectively. When we evaluated surgeons with more than 500 microsurgeries from the study by Ciric et al.3, the death rate was 0.2%, csf leak 1.5%, meningitis 0.5%, vascular complication (carotid artery injury + hemorrhage residual tumor) 1.2%, visual loss 0.5%, diabetes insipidus 7.6%, hypopituitarism 7.2%. Thus, with respect to vascular complications, death, diabetes insipidus, and hypopituitarism, the microsurgery group turned out to be a select group of patients with results superior to those obtained by highly experienced microsurgery specialists. This result could be due to many reasons, such as those suggested above, including: a series of patients with a high incidence of microadenomas; inclusion of endoscopy-assisted cases in the microsurgery group; the long tradition and evolution of microsurgery since the 1950s versus the recent history of purely endoscopic techniques (first series reported in 1997); and the significant experience of microscopic surgeons whose numerous studies populated the meta-analysis. There were two microsurgery studies, which described sets of 1140 and 638 patients; meanwhile, eight microsurgery studies described the treatment of only functional tumors, and six of the reviewed studies included more than 50 acromegalies or Cushing's syndrome cases, implying that the surgeons in question treated a significant number of adenomas. On the other hand, only one endoscopic study had more than 200 patients. If we compare the group of surgeons with less than 200 microscopic surgeries from the study by Ciric et al. (results: death rate 1.2%, csf leak 4.2%, meningitis 1.9%, vascular complication 4.2%, visual loss 2.4%, diabetes insipidus 19%, hypopituitarism 20,6%), with the metaanalisis endoscopic group, results strongly favor endoscopy. Nevertheless, the rates of complete resection, hypopituitarism, diabetes insipidus, meningitis, and nerve damage were all better for patients treated purely endoscopically, although without statistical significance. The authors of the review study criticize prior meta-analyses for being biased toward endoscopy based solely on the argument of fewer included patients; but they did not take into account their own inclusion criteria, which were more restrictive, considering only studies comparing both techniques, but not those using endoscopy- assisted microsurgery or those without complete outcomes that would enable better data ?interpretation and more solid and reliable results. In short, reading this study in isolation can lead to erroneous conclusions given the aforementioned biases and limitations.

Reference

1. Ciric I, Ragin A, Baumgartner C, et al. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225-37.

2. 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.

3. Zhang X, Fei Z, Zhang W, et al. Endoscopic endonasal transsphenoidal surgery for invasive pituitary adenoma. J Clin Neurosci 2008;15:241-5.

Conflict of Interest:

None declared

Dear Editor,

We would like to contribute on the article entitled “Radiological findings in individuals at high risk of schizophrenia and patients with first episode psychosis” by Borgwardt et al. [1] and on a letter by the same group [2], in which they comment on our own paper investigating this issue [3]. The authors highlight that they have found [1] a lower prevalence of cavum septum pellucidum (CSP) both in subjects with first-episode schizophrenia (3.3%) and individuals at high risk for psychosis (5.7%), when compared to our findings in schizophrenic patients (21.1%).

We agree with Borgwardt et al. [2] that their use of a qualitative rather than a quantitative method may explain their finding of a lower estimated frequency of CSP. We would also argue that the acquisition of high-resolution, 1-mm contiguous MRI brain slices in our study may have led to a more accurate estimation of the prevalence of CSP, as well as allowing the quantitative assessment of their size. Borgwardt et al. [2] also stressed the value of searching for a wider range of structural brain anomalies in psychosis, instead of focusing on a single abnormality, such as the CSP. In regard to that, MRI images in our study [3] were also inspected visually for the presence of other gross anomalies in midline brain structures, by a consensus between two neuroradiologists blind to sex, diagnosis and clinical status of subjects. At this assessment, one of the patients with schizophrenia was found to have a lipoma adherent to the anterior face of the splenium of the corpus callosum; one other case presented a parietal hemangioma, another patient presented total agenesis of the corpus callosum, while a fourth patient had a complete non-fusion of the entire length of the septum pellucidum – an anomaly termed ‘combined CSP and cavum vergae’. None of the observed abnormalities implicated in a change in the diagnosis from DSM-IV schizophrenia to psychotic disorder due to an ‘organic’ medical condition. We did not find any other gross or pathological midline abnormalities in any of the subjects studied. However, the following normal or minor brain variations were additionally found (data not presented before), only in the schizophrenia group: asymetrical ventricular system (n=4) and presence of arachnoid cyst (n=1). Thus, taking all those findings together, it is possible to conclude that in our sample, there is also a significantly (p = 0.001) higher proportion of radiological findings in patients with schizophrenia (9 of 38 or 23.7%) compared to healthy controls (none of 38). Although this was not the main objective of our study and the qualitative MRI assessment we have used was not standardized, our results are supportive of the findings reported by Borgwardt et al. [1] We suggest that future MRI studies, instead of focusing on either qualitative or quantitative assessments only, should systematically employ both approaches to evaluate the same sample. This may be of greater help for our understanding of the role of developmental anomalies in the neuropathology of schizophrenia.

References

[1] S.J. Borgwardt, E.W. Radue, K. Götz, et al., Radiological findings in individuals at high risk of schizophrenia and patients with first episode psychosis. J Neurol Neurosurg Psychiatry 2006;77:229–33.

[2] Borgwardt SJ, Radue EW, Riecher-Rossler A. Cavum septum pellucidum in patients with first episode psychosis and individuals at high risk of psychosis. Eur Psychiatry 2006; 22:264.

[3] J.A. De Souza Crippa, A.W. Zuardi, G.F. Busatto, et al., Cavum septum pellucidum and adhesio interthalamica in schizophrenia: an MRI study. Eur Psychiatry 2006; 21: 291–9.

Competing interest: None