Down syndrome

Down syndrome

Down syndrome is a multiple malformation syndrome due to the trisomy of chromosome 21.

Down syndrome may be associated with various neurologic complications such as moyamoya disease, cervical spinal cord compression due to atlanto-axial subluxation, and basal ganglia damage, as well as epileptic seizures and stroke 1).


Down syndrome is associated with ligamentous laxity of the spine. This has implications whenever a fusion is contemplated, as adjacent segment failure with kyphosis is very common. Ligamentous laxity may also result in atlanto-axial subluxation (AAS).

Atlanto-axial subluxation in Down syndrome

(Cerebral) amyloid angiopathy may be more prevalent in patients with Down syndrome.


Many cases of Down syndrome accompanied by isolated neurologic manifestations have been reported in children; however, Down syndrome with multiple neurologic conditions is rare 2).

There is epidemiological evidence that individuals with Down syndrome are at decreased risk for solid tumors including brain tumors. It has been suggested that some genes expressed on the extra copy of chromosome 21 act as tumor suppressor genes and contribute to the protection against tumorigenesis.

Yolk sac tumor 3)

Yamamoto et al. report the first Down syndrome patient, an 8-year-old boy, with a meningioma in the posterior fossa. The diagnosis was based on histological study of the surgically resected tumor. Postoperatively his neurological status improved and there was no tumor regrowth in the next 2 years. Fluorescence in situ hybridization (FISH) for chromosome 22 confirmed high allele loss involving the NF2 gene locus, a finding typical in meningiomas. FISH also revealed chromosome 21 heterogeneity in tumor cells; not only cells with trisomy 21 but also cells with disomy and monosomy 21 were present. All blood cells from the patient manifested trisomy 21.

This finding suggests that deletion of the chromosome 21 allele may be associated with the tumorigenesis of meningioma in Down syndrome. It supports the hypothesis that some genes whose expression is increased on the extra copy of chromosome 21 function as tumor suppressor genes and that they contribute to the reduced tumor incidence in individuals with Down syndrome 4).

Down syndrome (DS) patients with early-onset dementia share similar neurodegenerative features with Alzheimer disease (AD) 5).

Individuals with Down syndrome (DS) are at increased risk of developing AD in adulthood as a result of chromosome 21 trisomy and triplication of the amyloid precursor protein (APP) gene. In both conditions, the central nervous system (CNS) basal forebrain cholinergic system progressively degenerates, and such changes contribute to the manifestation of cognitive decline and dementia. Given the strong dependency of these neurons on nerve growth factor (NGF), it was hypothesized that their atrophy was caused by NGF deficits. However, in AD, the synthesis of NGF is not affected at the transcript level and there is a marked increase in its precursor, proNGF. This apparent paradox remained elusive for many years 6).


Down syndrome results in neuromotor impairment that affects selective motor control, compromising the acquisition of motor skills and functional independence.

A study received approval from the Institutional Review Board of Universidade Nove de Julho (Sao Paulo,Brazil) under process number 1.540.113 and is registered with the Brazilian Registry of Clinical Trials (N° RBR3PHPXB). The participating institutions have presented a declaration of participation. The volunteers will be permitted to drop out of the study at any time with no negative repercussions. The results will be published and will contribute evidence regarding the use of this type of intervention on children 7).

Cervical spine pathologies are common in Down syndrome (DS) patients. Cervical pathologies may cause cord compression and neurologic deterioration if left untreated. Complication rates of 73-100% have been reported in DS patients after cervical spine surgery in historical studies.

Current techniques may improve pseudarthrosis (p = 0.009), LOR (p = 0.043), and first attempt (p = 0.038) and overall fusion rates (p = 0.018) compared with historical studies. Complications continue to challenge most patients (82.4%). A total of 16 of 17 patients (94.1%) demonstrated stabilization or improvement in neurologic status. Apparent successful outcome in the majority appears to warrant the high complication risk associated with cervical spine surgery in DS patients. The anterior approach resulted in a higher risk of complications than posterior (p = 0.032). Siemionow et al report a higher than expected incidence of pseudarthrosis in DS patients receiving rhBMP-2, putting its benefit in DS patients into question 8).

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1)

Hwang SW, Jea A. A review of the neurological and neurosurgical implications of Down syndrome in children. Clin Pediatr (Phila). 2013 Sep;52(9):845-56. doi: 10.1177/0009922813491311. Epub 2013 Jun 6. Review. PubMed PMID: 23743011.
2)

Lee KY, Lee KS, Weon YC. Asymptomatic moyamoya syndrome, atlantoaxial subluxation and basal ganglia calcification in a child with Down syndrome. Korean J Pediatr. 2013 Dec;56(12):540-3. doi: 10.3345/kjp.2013.56.12.540. Epub 2013 Dec 20. PubMed PMID: 24416050; PubMed Central PMCID: PMC3885790.
3)

Sugimoto K, Ideguchi M, Sadahiro H, Yoshikawa K, Goto H, Nomura S, Fujii M, Suzuki M. Yolk sac tumor of the bilateral basal ganglia in a patient with Down syndrome. Brain Tumor Pathol. 2013 Oct;30(4):247-52. doi: 10.1007/s10014-012-0134-9. Epub 2013 Jan 11. Review. PubMed PMID: 23306965.
4)

Yamamoto T, Shinojima N, Todaka T, Nishikawa S, Yano S, Kuratsu JI. Meningioma in Down syndrome – Case Report. World Neurosurg. 2015 Apr 8. pii: S1878-8750(15)00365-4. doi: 10.1016/j.wneu.2015.03.065. [Epub ahead of print] PubMed PMID: 25862935.
5)

Chang CY, Chen SM, Lu HE, Lai SM, Lai PS, Shen PW, Chen PY, Shen CI, Harn HJ, Lin SZ, Hwang SM, Su HL. N-butylidenephthalide Attenuates Alzheimer’s Disease-Like Cytopathy in Down Syndrome Induced Pluripotent Stem Cell-Derived Neurons. Sci Rep. 2015 Mar 4;5:8744. doi: 10.1038/srep08744. PubMed PMID: 25735452; PubMed Central PMCID: PMC4348654.
6)

Iulita MF, Cuello AC. Nerve growth factor metabolic dysfunction in Alzheimer’s disease and Down syndrome. Trends Pharmacol Sci. 2014 Jul;35(7):338-48. doi: 10.1016/j.tips.2014.04.010. Epub 2014 Jun 21. Review. PubMed PMID: 24962069.
7)

Lopes JBP, Grecco LAC, Moura RCF, Lazzari RD, Duarte NAC, Miziara I, Melo GEL, Dumont AJL, Galli M, Santos Oliveira C. Protocol study for a randomised, controlled, double-blind, clinical trial involving virtual reality and anodal transcranial direct current stimulation for the improvement of upper limb motor function in children with Down syndrome. BMJ Open. 2017 Aug 11;7(8):e016260. doi: 10.1136/bmjopen-2017-016260. PubMed PMID: 28801420.
8)

Siemionow K, Hansdorfer M, Janusz P, Mardjetko S. Complications in Adult Patients with Down Syndrome Undergoing Cervical Spine Surgery Using Current Instrumentation Techniques and rhBMP-2: A Long-Term Follow-Up. J Neurol Surg A Cent Eur Neurosurg. 2016 Jul 22. [Epub ahead of print] PubMed PMID: 27448197.

Deep brain stimulation for Meige syndrome

Deep brain stimulation for Meige syndrome

A well-established therapeutic option is deep brain stimulation (DBS), and the target in bilateral globus pallidus internus (GPi DBS) demonstrated satisfactory short- and long-term efficacy. However, some patients present minor or suboptimal responses after GPi DBS, and in those cases, rescue DBS may be appropriate 1).


A retrospective study to assess the efficacy and safety of bilateral GPi stimulation in 40 patients with primary Meige syndrome who responded poorly to medical treatments or botulinum toxin injections. All participants were postoperatively followed up at the outpatient clinic, and their motor functions were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The severity of patients’ dystonia was evaluated before surgery and at follow-up neurostimu-lation.

Results: The implanted stimulator was turned on 1 month after surgery. All 40 patients received monopolar stimulation using the following parameters: voltage 2.5-3.5 V (average: 2.6 ± 0.8 V), frequency 60-160 Hz (average: 88.0 ± 21.3 Hz), and pulse width 60-185 μS (average: 90.0 ± 21.1 μS). In 28 of 40 patients, the symptoms had signifi-cantly improved within 1 week of stimulation. Most of the patients had been followed up for 6-24 months (average: 15.0 ± 7.8 months). The clinical symptoms of all patients had significantly improved. At 6, 12, and 24 months after surgery, the BFMDRS subscores of eyes, mouth, speech, and swallowing were significantly lower, and subscores of mouth movement showed progressively decreased with prolonged stimulation time. The overall improvement rate was 83%. Five adverse events occurred in the 40 patients; all of these events resolved without permanent sequelae.

Bilateral GPi-DBS demonstrated satisfactory long-term efficacy in the treatment of primary Meige syndrome and could serve as an effective and safe option 2).


A study explored the predictors of clinical outcome in patients with Meige syndrome who underwent DBS.

Twenty patients who underwent DBS targeting the bilateral subthalamic nucleus (STN) or globus pallidus internus (GPi) at the Chinese People’s Liberation Army General Hospital from August 2013 to February 2018 were enrolled in the study. Their clinical outcomes were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale at baseline and at the follow-up visits; patients were accordingly divided into a good-outcome group and a poor-outcome group. Putative influential factors, such as age and course of disease, were examined separately, and the factors that reached statistical significance were subjected to logistic regression analysis to identify predictors of clinical outcomes.

Four factors showed significant differences between the good- and poor-outcome groups: 1) the DBS target (STN vs GPi); 2) whether symptoms first appeared at multiple sites or at a single site; 3) the sub-item scores of the mouth at baseline; and 4) the follow-up period (p < 0.05). Binary logistic regression analysis revealed that initial involvement of multiple sites and the mouth score were the only significant predictors of clinical outcome.

The severity of the disease in the initial stage and presurgical period was the only independent predictive factor of the clinical outcomes of DBS for the treatment of patients with Meige syndrome 3).


A total of 6 patients seen between 2002 and 2010 with craniofacial and craniocervical dystonia symptoms were identified from the University of Florida Institutional Review Board approved database. Patients were videotaped using a standardized protocol, and tapes were randomized and blindly reviewed by a movement disorders neurologist. The Unified Dystonia Rating Scale improved 31.6 ± 23.2% (range: 3.4-63.2%) at 6 months and 63.7 ± 35.3% (range: 6.3-100%) at 12 months. The Burke-Fahn-Marsden Dystonia Rating Scale improved 45.3 ± 29.5% (range: 4.7-75.0%) at 6 months and 61.8 ± 30.9% (range: 16.6-100%) at 12 months. One patient significantly had a very large improvement with little evidence of residual dystonia. Blepharospasm improved in all patients, whereas speech and swallowing did not improve in this cohort. Two patients improved with unilateral GPi-DBS, although one required a contralateral DBS later in the disease course. Two patients were managed with low-frequency stimulation (<100 Hz). Two patients had less than 20% benefit. GPi-DBS for cranio-facial and craniocervical symptoms is an effective strategy to manage a subset of patients who remain unresponsive to optimized medical management. Unilateral stimulation may be an option for some patients, but it remains unclear whether response to single-sided stimulation will be sustainable. The mixed results of this GPi-DBS case series highlight the need for a careful re-examination of selection criteria, alternative brain targets, and possibly rescue leads for patients who are non-responders to the GPi target 4).


Lyons report the long-term results of bilateral globus pallidus internus (GPi) or subthalamic nucleus (STN) stimulation in 3 patients with Meige syndrome and 1 patient with Parkinson’s disease and associated craniofacial dystonia treated at their center.

Initial 12-month and long-term follow-up Burke-Fahn-Marsden scores were substantially improved in all 4 patients compared with preoperative scores.

Bilateral GPi DBS may be an effective and safe treatment for medically refractory Meige syndrome. The results are comparable with those reported in the literature. Sustained and long-term improvement in symptoms does appear to be reproducible across reports. The authors’ patient with Parkinson’s disease and associated craniofacial dystonia syndrome undergoing bilateral STN DBS noted immediate and sustained improvement in his symptoms. Further study is required, but these results, along with the other reports, suggest that bilateral GPi DBS is an effective treatment for medically refractory Meige syndrome 5).


Sobstyl M, Ząbek M, Mossakowski Z, Zaczyński A. Pallidal deep brain stimulation in the treatment of Meige syndrome. Neurol Neurochir Pol. 2014;48(3):196-9. doi: 10.1016/j.pjnns.2014.05.008. Epub 2014 Jun 6. PubMed PMID: 24981184.


1)

Aragão VT, Barbosa Casagrande SC, Listik C, Teixeira MJ, Barbosa ER, Cury RG. Rescue Subthalamic Deep Brain Stimulation for Refractory Meige Syndrome. Stereotact Funct Neurosurg. 2021 Apr 23:1-3. doi: 10.1159/000515722. Epub ahead of print. PMID: 33895729.
2)

Tian H, Yu Y, Zhen X, Zhang L, Yuan Y, Zhang B, Wang L. Long-Term Efficacy of Deep Brain Stimulation of Bilateral Globus Pallidus Internus in Primary Meige Syndrome. Stereotact Funct Neurosurg. 2019;97(5-6):356-361. doi: 10.1159/000504861. Epub 2020 Jan 10. PMID: 31927550.
3)

Wang X, Mao Z, Cui Z, Xu X, Pan L, Liang S, Ling Z, Yu X. Predictive factors for long-term clinical outcomes of deep brain stimulation in the treatment of primary Meige syndrome. J Neurosurg. 2019 Apr 5:1-9. doi: 10.3171/2019.1.JNS182555. [Epub ahead of print] PubMed PMID: 30952124.
4)

Limotai N, Go C, Oyama G, Hwynn N, Zesiewicz T, Foote K, Bhidayasiri R, Malaty I, Zeilman P, Rodriguez R, Okun MS. Mixed results for GPi-DBS in the treatment of cranio-facial and cranio-cervical dystonia symptoms. J Neurol. 2011 Nov;258(11):2069-74. doi: 10.1007/s00415-011-6075-0. Epub 2011 May 7. PMID: 21553081.
5)

Lyons MK, Birch BD, Hillman RA, Boucher OK, Evidente VG. Long-term follow-up of deep brain stimulation for Meige syndrome. Neurosurg Focus. 2010 Aug;29(2):E5. doi: 10.3171/2010.4.FOCUS1067. PMID: 20672922.

Knobloch syndrome

Knobloch syndrome

Knobloch syndrome (KS) is a rare autosomal recessive disorder associated with multiple ocular and cranial abnormalities. Occult occipital skull defect or encephalocele should raise suspicion of this disease. It is never reported in neurosurgical literature, possibly due to a lack of clinician familiarity, leading to underdiagnosis and inadequate management.


Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, Caglayan et al. investigated the protein expression pattern of COL18A1 in the mid-fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database.

They identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. On further investigation of these patients and their families, they found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. This data strongly support an important role for COL18A1 in brain development, and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII.

This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology-allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. They suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1 mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of an encephalocele 1).


Venkateshappa reported a patient that also had seizures, which is a sporadic presentation of this syndrome.

They report a clinico-radiologic finding of a 7-year-old boy who presented with seizures, cataracts, and an occipital bone defect along with bilateral subependymal heterotopias and polymicrogyria.

This case highlights the importance of consideration of this syndrome in children with a midline occipital bone defect with or without encephalocele and seizures. Early recognition of this presentation is critical for obtaining access to appropriate genetic counseling and subsequent monitoring and prevention of complications by surgical intervention 2).


1)

Caglayan AO, Baranoski JF, Aktar F, Han W, Tuysuz B, Guzel A, Guclu B, Kaymakcalan H, Aktekin B, Akgumus GT, Murray PB, Erson-Omay EZ, Caglar C, Bakircioglu M, Sakalar YB, Guzel E, Demir N, Tuncer O, Senturk S, Ekici B, Minja FJ, Šestan N, Yasuno K, Bilguvar K, Caksen H, Gunel M. Brain malformations associated with Knobloch syndrome–review of literature, expanding clinical spectrum, and identification of novel mutations. Pediatr Neurol. 2014 Dec;51(6):806-813.e8. doi: 10.1016/j.pediatrneurol.2014.08.025. Epub 2014 Sep 4. PMID: 25456301; PMCID: PMC5056964.
2)

Venkateshappa BM, Raju B, Rallo MS, Jumah F, Suresh SC, Gupta G, Nanda A. Knobloch Syndrome, a Rare Cause of Occipital Encephalocele and Seizures: A Case Report. Pediatr Neurosurg. 2021 Mar 31:1-5. doi: 10.1159/000512719. Epub ahead of print. PMID: 33789317.
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