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.

Reversible cerebral vasoconstriction syndrome

Reversible cerebral vasoconstriction syndrome

Reversible cerebral vasoconstriction syndrome (RCVS), AKA Call-Fleming syndrome, 1) a group of disorders sharing the cardinal clinical and angiographic features of reversible segmental multifocal cerebral vasoconstriction with severe headaches, focal ischemia, and/or seizures. May present as a hemorrhage restricted to a cortical sulcus

Epidemiology

RCVS has been reported to occur more frequently in women aged 20 to 50 years.

Etiology

Several mechanisms have been postulated involving transient deregulation of cerebral arterial tone, small vessel endothelial dysfunction, biochemical factors, hormonal deregulation, oxidative stress, and genetic predisposition. All these mechanisms and triggers are related with sympathetic over-activation which eventually produce vasoconstriction. RCVS is distinguished by acute severe recurrent thunderclap headaches with or without other neurological symptoms. However, the diagnosis can be challenging and most likely underdiagnosed requiring a high level of suspicion from the clinician 2).

Clinical features

Reversible cerebral vasoconstriction syndrome (RCVS) has emerged as the most frequent cause of thunderclap headache (TCH) in patients without aneurysmal subarachnoid hemorrhage, and as the most frequent cause of recurrent TCHs.

The typical TCHs of RCVS are multiple, recurring over a few days to weeks, excruciating, short-lived, and brought up by exertion, sexual activities, emotion, Valsalva maneuvers, or bathing, among other triggers. All these triggers induce sympathetic activation. In a minority of cases with RCVS, TCH heralds stroke and rarely death. Early diagnosis of RCVS in patients who present with isolated headache enables proper management and might reduce the risk of eventual stroke 3).

Outcome

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headache and diffuse segmental constriction of cerebral arteries that resolves spontaneously within a few months. Although manifestations of stroke are not included in diagnostic criteria of RCVS, it is known that some cases may be associated with stroke, including intracerebral hemorrhage, subarachnoid hemorrhage, or cerebral infarction.


Intracerebral hemorrhage is the most common vascular complication in hospitalized RCVS patients, resulting in longer hospitalizations with more invasive procedures and higher healthcare expenditure. However, overall outcomes are excellent regardless of types of ICH, with no inpatient mortality observed in patients with hemorrhagic RCVS. Female sex and middle to older age-group are associated with higher odds of ICH. 4).

Case series

162 patients with RCVS. Clinical, brain imaging, and angiography data were analyzed.

The mean age was 44±13 years, 78% women. Hemorrhages occurred in 43% including 21 patients with intracerebral hemorrhage (ICH) and 62 with convexal subarachnoid hemorrhage (cSAH). The frequency of triggers (eg, vasoconstrictive drugs) and risk factors (eg, migraine) were not significantly different between hemorrhagic and nonhemorrhagic RCVS or between subgroups (ICH versus non-ICH, isolated cSAH versus normal scan). Hemorrhagic lesions occurred within the first week, whereas infarcts and vasogenic edema accumulated during 2 to 3 weeks (P<0.001). Although all ICHs occurred before cSAH, their time course was not significantly different (P=0.11). ICH and cSAH occurred earlier than infarcts (P≤0.001), and ICH earlier than vasogenic edema (P=0.009). Angiogram analysis showed more severe vasoconstriction in distal versus proximal segments in all lesion types (ICH, cSAH, infarction, vasogenic edema, and normal scan). The isolated infarction group had more severe proximal vasoconstriction, and those with normal imaging had significantly less vasoconstriction. Multivariable analysis failed to uncover independent predictors of hemorrhagic RCVS; however, female sex predicted ICH (P=0.048), and angiographic severity predicted infarction (P=0.043).

ICH and cSAH are common complications of RCVS. Triggers and risk factors do not predict lesion subtype but may alter central vasomotor control mechanisms resulting in centripetal angiographic evolution. Early distal vasoconstriction is associated with lobar ICH and cSAH, and delayed proximal vasoconstriction with infarction 5).

Case reports

2018

Reversible Cerebral Vasoconstriction Syndrome Without Typical Thunderclap Headache Complicated by Intracranial Hemorrhage and Posterior Reversible Encephalopathy Syndrome:A Case Report 6).


Al-Mufti et al. from the Rutgers New Jersey Medical School, describe a case of medically refractory Reversible cerebral vasoconstriction syndrome (RCVS) that required treatment with intra-arterial (IA) verapamil and subsequent nimodipine, resulting in both angiographic and clinical improvement after failing to respond to hemodynamic augmentation.

They also supplement a description of the case with a review of other case studies and case series in which IA calcium channel blockers were used to treat RCVS. They propose that the case they outline demonstrates that neurointerventional management with IA verapamil is appropriate and effective as an early intervention of medically refractory RCVS.

Using PubMed and Google Scholar, they performed a search of the English language literature with several combinations of the keywords “intra-arterial”, “calcium channel blockers”, “reversible cerebral vasoconstriction syndrome”, “RCVS”, “nimodipine”, “verapamil”, “milrinone”, and “nicardipine” to identify studies in which RCVS was treated with IA calcium channel blockers.

They identified eight case studies and case series that met our inclusion criteria. Eighteen patients are encompassed in these eight studies.

IA administration of calcium channel blockers has been shown to return cerebral vessels to their normal caliber in patients with medically refractory RCVS. However, there are no randomized controlled trials of the treatment of RCVS, and further studies are needed to elucidate the optimal treatment protocol for medically refractory RCVS 7).


Gonsales et al., present an unusual case of an 18-year-old female who developed RCVS after embolization of a dural arteriovenous fistula with onyx embolic material. A cerebral angiogram was performed and verapamil was administered intra-arterially demonstrating slight improvement of the constricted vessels with clinical improvement. The patient was maintained on oral verapamil during hospitalization. At 7-month follow-up, the patient was neurologically stable and a cerebral angiogram demonstrated no signs of vasoconstriction.

Endovascular procedures are a rare trigger for the development of RCVS and may be misdiagnosed. Prompt recognition of symptoms and diagnosis with treatment are necessary to reduce the risk of stroke. The management should follow the premise of discontinuing precipitating drugs and administering CCBs 8).

2016

A 19-year-old woman had a thunderclap headache, followed by left hemiparesis and left homonymous hemianopsia. Laboratory tests showed no signs of infection and immunological test results were unremarkable. MRI revealed a cerebral infarction in the right posterior cerebral artery territory, and digital subtraction angiography(DSA)showed right posterior cerebral artery stenosis on day 2. The first follow-up DSA demonstrated an irregular, bead-like appearance on day 9, but the stenotic lesion returned to normal on day 21. Reversible cerebral vasoconstriction syndrome should be suspected in cases of rapid resolution of symptoms 9).

2014

Ishi et al. present three cases of RCVS associated with various types of stroke, and then review the literature. Case 1:A 49-year-old woman presented with a headache followed by left hemiparesis and dysarthria. One month before the onset, she was transfused for severe anemia caused by uterus myoma. CT images revealed intracerebral hemorrhages in the right putamen and right occipital lobe. Angiography revealed multiple segmental constrictions of the cerebral arteries. One month after the onset, these vasoconstrictions improved spontaneously. Case 2:A postpartum 38-year-old woman who had a history of migraine presented with thunderclap headache. Imaging revealed a focal subarachnoid hemorrhage in the right postcentral sulcus and segmental vasoconstriction of the right middle cerebral artery. One week after the onset, this vasoconstriction improved spontaneously. Case 3:A 32-year-old woman who had a history of migraine presented with headache followed by left homonymous hemianopsia. Imaging revealed a cerebral infarction of the right occipital lobe and multiple constrictions of the right posterior cerebral artery. These vasoconstrictions gradually improved spontaneously 10).

References

1)

Call GK, Fleming MC, Sealfon S, et al. Reversible cerebral segmental vasoconstriction. Stroke. 1988; 19:1159–1170
2) , 8)

Gonsales D, das Gracas F, Santos R, Aguilar-Salinas P, Hanel RA. Reversible Cerebral Vasoconstriction Syndrome as an Unusual Complication of a Dural Arteriovenous Fistula treated with Onyx Embolization. World Neurosurg. 2018 May 8. pii: S1878-8750(18)30931-8. doi: 10.1016/j.wneu.2018.04.211. [Epub ahead of print] PubMed PMID: 29751188.
3)

Ducros A, Wolff V. The Typical Thunderclap Headache of Reversible Cerebral Vasoconstriction Syndrome and its Various Triggers. Headache. 2016 Apr;56(4):657-73. doi: 10.1111/head.12797. Epub 2016 Mar 26. Review. PubMed PMID: 27015869.
4)

Patel SD, Topiwala K, Saini V, et al. Hemorrhagic reversible cerebral vasoconstriction syndrome: A retrospective observational study [published online ahead of print, 2020 Sep 7]. J Neurol. 2020;10.1007/s00415-020-10193-y. doi:10.1007/s00415-020-10193-y
5)

Topcuoglu MA, Singhal AB. Hemorrhagic Reversible Cerebral Vasoconstriction Syndrome: Features and Mechanisms. Stroke. 2016 Jun 7. pii: STROKEAHA.116.013136. [Epub ahead of print] PubMed PMID: 27272485.
6)

Miki K, Takemoto K, Morishita T, Kouzaki Y, Irie Y, Iwaasa M, Abe H, Inoue T. [Reversible Cerebral Vasoconstriction Syndrome Without Typical Thunderclap Headache Complicated by Intracranial Hemorrhage and Posterior Reversible Encephalopathy Syndrome:A Case Report]. No Shinkei Geka. 2018 Dec;46(12):1111-1115. doi: 10.11477/mf.1436203877. Japanese. PubMed PMID: 30572309.
7)

Al-Mufti F, Dodson V, Wajswol E, El-Ghanem M, Alchaki A, Nuoman R, Thabet A, Sutherland A, Roychowdhury S, Hidalgo A, Gupta G. Chemical angioplasty for medically refractory reversible cerebral vasoconstriction syndrome(). Br J Neurosurg. 2018 Sep 12:1-5. doi: 10.1080/02688697.2018.1479512. [Epub ahead of print] PubMed PMID: 30207193.
9)

Koh M, Tsuboi Y, Fukuda O. [A Case of Juvenile Cerebral Infarction due to Reversible Cerebral Vasoconstriction Syndrome]. No Shinkei Geka. 2016 Nov;44(11):965-969. Japanese. PubMed PMID: 27832620.
10)

Ishi Y, Sugiyama T, Echizenya S, Yokoyama Y, Asaoka K, Itamoto K. [Reversible cerebral vasoconstriction syndrome associated with stroke: three case reports]. No Shinkei Geka. 2014 Feb;42(2):129-36. Japanese. PubMed PMID: 24501186.

Pallidal Deep Brain Stimulation for Lance-Adams syndrome

Pallidal Deep Brain Stimulation for Lance-Adams syndrome

A 79-year-old woman presented with a history of cardiac arrest due to internal carotid artery rupture following carotid endarterectomy after successful cardiopulmonary resuscitation. However, within 1 month, the patient developed sensory stimulation-induced myoclonus in her face and extremities. Because her myoclonic symptoms were refractory to pharmacotherapy, deep brain stimulation of the GPi was performed 1 year after the hypoxic attack.

Continuous bilateral Pallidal Deep Brain Stimulation with optimal parameter settings remarkably improved the patient’s myoclonic symptoms. At the 2-year follow-up, her Unified Myoclonus Rating Scale score decreased from 90 to 24. In addition, Mure et al. observed burst firing and interburst pause patterns on intraoperative microelectrode recordings of the bilateral GPi and stimulated this area as the therapeutic target.

The results show that impairment in the basal ganglion circuitry might be involved in the pathogenesis of myoclonus in patients with Lance-Adams syndrome 1).


A 23-year-old male with chronic medication refractory PHM following a cardiopulmonary arrest related to an asthmatic attack who improved with bilateral globus pallidus internus (GPi) deep brain stimulation (DBS). Ramdhani et al. reviewed the clinical features of PHM, as well as the preoperative and postoperative Unified Myoclonus Rating Scale scores and DBS programming parameters in this patient and compare them with the three other published PHM-DBS cases in the literature.

This patient experienced an alleviation of myoclonic jerks at rest and a 39% reduction in action myoclonus with improvement in both positive and negative myoclonus with bilateral GPi-DBS. High frequency stimulation (130 Hz) with amplitudes >2.5 V were needed for the therapeutic response.

They demonstrated a robust improvement in a medication refractory PHM patient with bilateral GPi-DBS, and suggest that it is a viable therapeutic option for debilitating post-hypoxic myoclonus 2).


The first case of a patient who developed action myoclonus after experiencing perinatal anoxia and was successfully treated by chronic deep brain stimulation (DBS) of the thalamus (thalamic DBS).

The effectiveness of chronic thalamic DBS in this patient supports the concept of involvement of the thalamus in post-perinatal anoxic myoclonus 3).


Asahi T, Kashiwazaki D, Dougu N, et al. Alleviation of myoclonus after bilateral pallidal deep brain stimulation for Lance-Adams syndrome. J Neurol. 2015;262(6):1581-1583. doi:10.1007/s00415-015-7748-x 4).


Yamada K, Sakurama T, Soyama N, Kuratsu J. Gpi pallidal stimulation for Lance-Adams syndrome. Neurology. 2011;76(14):1270-1272. doi:10.1212/WNL.0b013e31821482f4 5).

References

1)

Mure H, Toyoda N, Morigaki R, Fujita K, Takagi Y. Clinical Outcome and Intraoperative Neurophysiology of the Lance-Adams Syndrome Treated with Bilateral Deep Brain Stimulation of the Globus Pallidus Internus: A Case Report and Review of the Literature [published online ahead of print, 2020 Sep 7]. Stereotact Funct Neurosurg. 2020;1-5. doi:10.1159/000509318
2) , 3)

Ramdhani RA, Frucht SJ, Kopell BH. Improvement of Post-hypoxic Myoclonus with Bilateral Pallidal Deep Brain Stimulation: A Case Report and Review of the Literature. Tremor Other Hyperkinet Mov (N Y). 2017;7:461. Published 2017 May 19. doi:10.7916/D8NZ8DXP
4)

Asahi T, Kashiwazaki D, Dougu N, et al. Alleviation of myoclonus after bilateral pallidal deep brain stimulation for Lance-Adams syndrome. J Neurol. 2015;262(6):1581-1583. doi:10.1007/s00415-015-7748-x
5)

Yamada K, Sakurama T, Soyama N, Kuratsu J. Gpi pallidal stimulation for Lance-Adams syndrome. Neurology. 2011;76(14):1270-1272. doi:10.1212/WNL.0b013e31821482f4
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