Primary dystonia

Primary dystonia

Primary dystonia is a neurological disease with the characteristics of abnormal, involuntary twisting and turning movements, which greatly affects life quality of patients.

Primary dystonia is suspected when the dystonia is the only sign and there is no identifiable cause or structural abnormality in the central nervous system.

Primary Dystonia Etiology.

The dystonia pathophysiology is poorly understood. As opposed to secondary forms of dystoniaprimary dystonia has long been believed to lack any neuroanatomical substrate. During trajectory planning for DBS, however, conspicuous T2-hyperintense signal alterations (SA) were registered within the target region, even in young patients, where ischemia is rare.

Fifty MRIs of primary dystonia patients scheduled for DBS were analyzed. Total basal ganglia (BG) volumes, as well as proportionate SA volumes, were measured and compared to 50 age-matched control patients.

There was a 10-fold preponderance of percentaged SA within the globus pallidus (GP) in dystonia patients. The greatest disparity was in young patients <25 years. Also, total BG volume differences were observed with larger GP and markedly smaller putamen and caudate in the dystonia group.

BG morphology in primary dystonia differed from a control population. Volume reductions of the putamen and caudate may reflect functional degeneration, while volume increases of the GP may indicate overactivity. T2-hyperintensive SA in the GP of young primary dystonia patients, where microvascular lesions are highly unlikely, are striking. Their pathogenic role remains unclear 1).

Pallidal Deep Brain Stimulation is the primary surgical treatment for dystonia 2). The response is better for primary dystonias, e.g. tardive dystonias than for secondary dystonias such as postanoxic, postencephalitic, perinatal, and post-stroke dystonia 3) (other targets need to be assessed). For primary dystonias, the globus pallidus internus (GPi) is the most common primary target. Good results have also been reported with STN DBS. Dyskinetic cerebral palsy in children may also be treated with pallidal stimulation 4).


Treatments for dystonia consist of oral medications, botulinum neurotoxin injections, physical therapy and surgeries. For medication-refractory dystonia, surgeries, especially deep brain stimulation (DBS), are the optimal option.

Treatment response is better for primary dystonias than for secondary dystonias. 5).

A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in the early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), Wirth et al. aimed to identify the missing genetic causes in dystonic patients without a diagnosis despite gene panel sequencing.

WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature.

They identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002).

This approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia 6).

A 13-year-old boy suffering from extremely severe primary dystonia, with a BFMDRS-M score of 118 and a TWSTRS-S score of 29. The examination of 173 genes including DYT failed to identify any abnormality. He responded ineffectively to medications. After both bilateral subthalamic nucleus DBS and unilateral Vim-Vo thalamotomy (combined thalamic lesion in ventralis intermedius nucleus and ventralis oralis nucleus), his movement disorder improved dramatically. Four months and seven months after the operation, the scores of two rating scales sharply decreased. And potential brain structural changes were reflected in sensorimotor-related cortical thickness, surface area and gray matter volume from MRI, which revealed a valid method to evaluate surgical effect on the brain with enough patients.

DBS and thalamotomy is potentially an effective combination of treatments for severe medication-refractory dystonia 7).


1)

Bai X, Vajkoczy P, Faust K. Morphological Abnormalities in the Basal Ganglia of Dystonia Patients. Stereotact Funct Neurosurg. 2021 Jan 20:1-12. doi: 10.1159/000512599. Epub ahead of print. PMID: 33472209.
2) , 3)

Awan NR, Lozano A, Hamani C. Deep brain stimulation: current and future perspectives. Neurosurg Focus. 2009; 27. DOI: 10.3171/2009.4.FOCUS0982
4)

Keen JR, Przekop A, Olaya JE, et al. Deep brain sti- mulation for the treatment of childhood dystonic cerebral palsy. J Neurosurg Pediatr. 2014; 14: 585–593
5)

Awan NR, Lozano A, Hamani C. Deep brain stimulation: current and future perspectives. Neurosurg Focus. 2009 Jul;27(1):E2. doi: 10.3171/2009.4.FOCUS0982. Review. PubMed PMID: 19569890.
6)

Wirth T, Tranchant C, Drouot N, Keren B, Mignot C, Cif L, Lefaucheur R, Lion-François L, Méneret A, Gras D, Roze E, Laroche C, Burbaud P, Bannier S, Lagha-Boukbiza O, Spitz MA, Laugel V, Bereau M, Ollivier E, Nitschke P, Doummar D, Rudolf G, Anheim M, Chelly J. Increased diagnostic yield in complex dystonia through exome sequencing. Parkinsonism Relat Disord. 2020 Apr 20;74:50-56. doi: 10.1016/j.parkreldis.2020.04.003. [Epub ahead of print] PubMed PMID: 32334381.
7)

Lin H, Cai XD, Zhang DD, Liu JL, Li WP. Both DBS and Thalamotomy in a 13-year-old Patient with Primary Dystonia: A Case Report. World Neurosurg. 2018 Jun 8. pii: S1878-8750(18)31202-6. doi: 10.1016/j.wneu.2018.05.248. [Epub ahead of print] PubMed PMID: 29890276.

Lactotroph Adenoma Surgery

Lactotroph Adenoma Surgery

Lactotroph Adenoma Surgery is safe and efficient. It is particularly suitable for enclosed prolactinomas. The patient should be well informed of the pros and cons of the treatment options, which include dopamine agonist (DA) and transsphenoidal microsurgery, and the patient’s preference should be taken into account during decision-making 1).

In the majority of prolactinoma patients, disease remission can be achieved through surgery, with low risks of long-term surgical complications, and disease remission is less often achieved with dopamine agonist2).

Prolactin level < 500 ng/ml in prolactinomas that are not extensively invasive: PRL may be normalized with surgery.


PRL > 500 ng/ml: the chances of normalizing PRL surgically are very low 3).

If no acute progression, an initial attempt of medical therapy should be made as the chances of normalizing PRL surgically with preop levels > 500 ng/ml are very low 4) (these tumors may shrink dramatically with bromocriptine).

If tumor not controlled medically (≈ 18 % will not respond to bromocriptine: surgery followed by restitution of medical therapy may normalize PRL).


Barrow et al. reviewed the results of transsphenoidal microsurgical management in 69 patients with prolactin-secreting pituitary adenomas who had preoperative serum prolactin levels over 200 ng/ml. The patients were divided into three groups based on their preoperative serum prolactin levels: over 200 to 500 ng/ml (Group A); over 500 to 1000 ng/ml (Group B); and over 1000 ng/ml (Group C). The percentage of successful treatment (“control rate”) was 68%, 30%, and 14%, respectively, in these three groups of patients. Based on these results, the authors offer guidelines for the management of patients with prolactin-secreting pituitary adenomas associated with exceptionally high serum prolactin levels. The surgical control rate of 68% in Group A seems to justify surgery for these patients, while primary medical care with bromocriptine is recommended for most patients with serum prolactin levels over 500 ng/ml 5).


Dopamine agonist therapy is the first line of treatment for prolactinomas because of its effectiveness in normalizing serum prolactin levels and shrinking tumor size. Though withdrawal of dopamine agonist treatment is safe and may be implemented following certain recommendations, recurrence of disease after cessation of the drug occurs in a substantial proportion of patients. Concerns regarding the safety of dopamine agonists have been raised, but its safety profile remains high, allowing its use during pregnancy. Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or are experiencing progressive tumor growth. Surgical resection can also be considered as a primary treatment for those with smaller focal tumors where a biochemical cure can be expected as an alternative to lifelong dopamine agonist treatment. Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy 6).


Many guidelines and reports that caution against surgical treatment are based on data over a decade or more old using different techniques such as microsurgical transsphenoidal surgery or from the nascent era of endoscopic transphenoidal surgery 7).

Endoscopic techniques have continued to evolve and provide for excellent visualization, low CSF leak rates, and high rates of gross total resection. In a study of DA-resistant prolactinomas, Vroonen et al. showed that surgical debulking led to a significant de- crease in prolactin levels at a significantly lower DA dose 8).

Kreutzer et al. report a remission rate of 91 % in patients who had elective surgery of microprolactinomas, and Babey et al. also had a high long-term remission rate, without morbidity or mortality for patients with microprolactinomas 9) 10).

Cost considerations are also a concern, especially in countries such as the USA, which is undergoing rapid changes in its healthcare system. A study by Jethwa and Patel et al. found surgical resection of microprolactinomas to be more cost effective long term than medical therapy 11).


Tumor size and invasion of extrasellar and/or cavernous sinuses have typically been seen as limitations of surgery, and some patients with refractory very large or giant tumors may necessitate multistage surgical procedures with a combi- nation of endonasal and transcranial approaches.

see Lactotroph adenoma radiosurgery.


Expanded endoscopic endonasal techniques have been developed that allow for safe treatment of larger adenomas that have extra-/parasellar extension as long as the extension is in the cranio-caudal direction and not lateral to the carotids. However, the issue of partial resection and the risk of apoplexy in the residual irritated tumor is of some concern. As in many other areas of neuro-oncology, a combination approach may be optimal. Surgical resection may allow for definitive removal of the tumor and relief of the mass effect and provide tissue for precisely targeted therapies to prevent recurrence. Sophisticated immunohistochemistry and genetic testing are rapidly being applied to many other tumors and may in the future allow for superior targeted adjuvant therapies in prolactinomas and help reduce recurrences. Finally, surgery might be an answer to the long-term cost of medical therapy specifically in younger patients. However, this issue should be carefully assessed on an individual basis to not jeopardize the standard of care in prolactinoma management by unnecessary surgical treatment. Medical treatment remains the first and the treatment of choice in the general population with recently diagnosed prolactinoma in the absence of rapidly progressive neurological symptoms 12).

Few studies address the cost of treating prolactinomas.

The Department of Neurological Surgery, University of California at San Francisco, performed a cost-utility analysis of surgical versus medical treatment for prolactinomas. Materials and Methods We determined total hospital costs for surgically and medically treated prolactinoma patients. Decision-tree analysis was performed to determine which treatment produced the highest quality-adjusted life years (QALYs). Outcome data were derived from published studies. Results Average total costs for surgical patients were $19,224 ( ± 18,920). Average cost for the first year of bromocriptine or cabergoline treatment was $3,935 and $6,042, with $2,622 and $4,729 for each additional treatment year. For a patient diagnosed with prolactinoma at 40 years of age, surgery has the lowest lifetime cost ($40,473), followed by bromocriptine ($41,601) and cabergoline ($70,696). Surgery also appears to generate high health state utility and thus more QALYs. In sensitivity analyses, surgery appears to be a cost-effective treatment option for prolactinomas across a range of ages, medical/surgical costs, and medical/surgical response rates, except when surgical cure rates are ≤ 30%. Conclusion Our single institution analysis suggests that surgery may be a more cost-effective treatment for prolactinomas than medical management for a range of patient ages, costs, and response rates. Direct empirical comparison of QALYs for different treatment strategies is needed to confirm these findings 13).


1)

Giese S, Nasi-Kordhishti I, Honegger J. Outcomes of Transsphenoidal Microsurgery for Prolactinomas – A Contemporary Series of 162 Cases. Exp Clin Endocrinol Diabetes. 2021 Jan 18. doi: 10.1055/a-1247-4908. Epub ahead of print. PMID: 33461233.
2)

Zamanipoor Najafabadi AH, Zandbergen IM, de Vries F, et al. Surgery as a Viable Alternative First-Line Treatment for Prolactinoma Patients. A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2020;105(3):e32‐e41. doi:10.1210/clinem/dgz144
3) , 4) , 5)

Barrow DL, Mizuno J, Tindall GT. Management of prolactinomas associated with very high serum prolactin levels. J Neurosurg. 1988 Apr;68(4):554-8. PubMed PMID: 3351583.
6)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
7)

Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, Brue T, Cappabianca P, Colao A, Fahlbusch R, Fideleff H, Hadani M, Kelly P, Kleinberg D, Laws E, Marek J, Scanlon M, Sobrinho LG, Wass JA, Giustina A (2006) Guidelines of the pituitary society for the diagnosis and management of prolactinomas. Clin Endocrinol 65:265–273
8)

Vroonen L, Jaffrain-Rea ML, Petrossians P, Tamagno G, Chanson P, Vilar L, Borson-Chazot F, Naves LA, Brue T, Gatta B, Delemer B, Ciccarelli E, Beck-Peccoz P, Caron P, Daly AF, Beckers A (2012) Prolactinomas resistant to standard doses of cabergoline: a multicen- ter study of 92 patients. Eur J Endocrinol 167:651–662
9)

Babey M, Sahli R, Vajtai I, Andres RH, Seiler RW (2011) Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists. Pituitary 14:222–230
10)

Kreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky C, Fahlbusch R, Buchfelder M (2008) Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol 158:11–18
11)

Jethwa PR, Patel TD, Hajart AF, Eloy JA, Couldwell WT, Liu JK (2015) Cost-effectiveness analysis of microscopic and endoscopic transsphenoidal surgery versus medical therapy in the management of microprolactinoma in the United States. World Neurosurg 5:2015
12)

Chakraborty S, Dehdashti AR. Does the medical treatment for prolactinoma remain the standard of care? Acta Neurochir (Wien). 2016 May;158(5):943-4. doi: 10.1007/s00701-016-2763-y. Epub 2016 Mar 11. PubMed PMID: 26965287.
13)

Zygourakis CC, Imber BS, Chen R, Han SJ, Blevins L, Molinaro A, Kahn JG, Aghi MK. Cost-Effectiveness Analysis of Surgical versus Medical Treatment of Prolactinomas. J Neurol Surg B Skull Base. 2017 Apr;78(2):125-131. doi: 10.1055/s-0036-1592193. Epub 2016 Sep 27. PubMed PMID: 28321375; PubMed Central PMCID: PMC5357228.

Osteopontin in subarachnoid hemorrhage

Osteopontin in subarachnoid hemorrhage

Experimental studies reported that osteopontin (OPN), is induced in the brain after subarachnoid hemorrhage (SAH).

OPN may increase MAPK phosphatase-1 that inactivates MAPKs, upstream and downstream of vascular endothelial growth factor A, by binding to L-arginyl-glycyl-L-aspartate-dependent integrin receptors, suggesting a novel mechanism of OPN-induced post-SAH BBB protection 1).


The relationships between osteopontin (OPN) expression and chronic shunt-dependent hydrocephalus (SDHC) have never been investigated. In 166 SAH patients (derivation and validation cohorts, 110 and 56, respectively), plasma OPN levels were serially measured at days 1-3, 4-6, 7-9, and 10-12 after aneurysmal obliteration. The OPN levels and clinical factors were compared between patients with and without subsequent development of chronic SDHC. Plasma OPN levels in the SDHC patients increased from days 1-3 to days 4-6 and remained high thereafter, while those in the non-SDHC patients peaked at days 4-6 and then decreased over time. Plasma OPN levels had no correlation with serum levels of C-reactive protein (CRP), a systemic inflammatory marker. Univariate analyses showed that age, modified Fisher scaleacute hydrocephaluscerebrospinal fluid drainage, and OPN and CRP levels at days 10-12 were significantly different between patients with and without SDHC. Multivariate analyses revealed that higher plasma OPN levels at days 10-12 were an independent factor associated with the development of SDHC, in addition to the more frequent use of cerebrospinal fluid drainage and higher modified Fisher grade at admission. Plasma OPN levels at days 10-12 maintained similar discrimination power in the validation cohort and had good calibration on the Hosmer-Lemeshow goodness-of-fit test. Prolonged higher expression of OPN may contribute to the development of post-SAH SDHC, possibly by excessive repairing effects promoting fibrosis in the subarachnoid space 2).


Abate et al. included 44 patients with the following criteria: (1) age 18 and 80 years, (2) diagnosis of SAH from cerebral aneurysm rupture, (3) insertion of an external ventricular drain. Plasma and CSF were sampled at day 1, 4, and 8. OPN levels, in CSF and plasma, displayed a weak correlation on day 1 and were higher, in CSF, in all time points. Only in poor prognosis patients, OPN levels in CSF significantly increased at day 4 and day 8. Plasma OPN at day 1 and 4 was predictor of poor outcome. In conclusion, plasma and CSF OPN displays a weak correlation, on day 1. The higher levels of OPN found in the CSF compared to plasma, suggest OPN production within the CNS after SAH. Furthermore, plasma OPN, at day 1 and 4, seems to be an independent predictor of poor outcome 3).


The aim of the study was to investigate the relationships between plasma OPN levels and outcome after aneurysmal SAH in a clinical setting. This is a prospective study consisting of 109 aneurysmal SAH patients who underwent aneurysmal obliteration within 48 h of SAH. Plasma OPN concentrations were serially determined at days 1-3, 4-6, 7-9, and 10-12 after onset. Various clinical factors as well as OPN values were compared between patients with 90-day good and poor outcomes. Plasma OPN levels were significantly higher in SAH patients compared with control patients and peaked at days 4-6. Poor-outcome patients had significantly higher plasma OPN levels through all sampling points. Receiver-operating characteristic curves demonstrated that OPN levels at days 10-12 were the most useful predictor of poor outcome at cutoff values of 915.9 pmol/L (sensitivity, 0.694; specificity, 0.845). Multivariate analyses using the significant variables identified by day 3 showed that plasma OPN ≥ 955.1 pmol/L at days 1-3 (odds ratio, 10.336; 95% confidence interval, 2.563-56.077; p < 0.001) was an independent predictor of poor outcome, in addition to increasing age, preoperative World Federation of Neurological Surgeons grades IV-V, and modified Fisher grade 4. Post hoc analyses revealed no correlation between OPN levels and serum levels of C-reactive protein, a non-specific inflammatory parameter, at days 1-3. Acute-phase plasma OPN could be used as a useful prognostic biomarker in SAH 4).


1)

Suzuki H, Hasegawa Y, Kanamaru K, Zhang JH. Mechanisms of osteopontin-induced stabilization of blood-brain barrier disruption after subarachnoid hemorrhage in rats. Stroke. 2010 Aug;41(8):1783-90. doi: 10.1161/STROKEAHA.110.586537. Epub 2010 Jul 8. PMID: 20616319; PMCID: PMC2923856.
2)

Asada R, Nakatsuka Y, Kanamaru H, Kawakita F, Fujimoto M, Miura Y, Shiba M, Yasuda R, Toma N, Suzuki H; pSEED group. Higher Plasma Osteopontin Concentrations Associated with Subsequent Development of Chronic Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage. Transl Stroke Res. 2021 Jan 9. doi: 10.1007/s12975-020-00886-x. Epub ahead of print. PMID: 33423213.
3)

Abate MG, Moretto L, Licari I, Esposito T, Capuano L, Olivieri C, Benech A, Brucoli M, Avanzi GC, Cammarota G, Dianzani U, Clemente N, Panzarasa G, Citerio G, Carfagna F, Cappellano G, Della Corte F, Vaschetto R. Osteopontin in the Cerebrospinal Fluid of Patients with Severe Aneurysmal Subarachnoid Hemorrhage. Cells. 2019 Jul 10;8(7):695. doi: 10.3390/cells8070695. PMID: 31295895; PMCID: PMC6678172.
4)

Nakatsuka Y, Shiba M, Nishikawa H, Terashima M, Kawakita F, Fujimoto M, Suzuki H; pSEED group. Acute-Phase Plasma Osteopontin as an Independent Predictor for Poor Outcome After Aneurysmal Subarachnoid Hemorrhage. Mol Neurobiol. 2018 Jan 20. doi: 10.1007/s12035-018-0893-3. [Epub ahead of print] PubMed PMID: 29353454.
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