Neural glymphatic system: Clinical implications and potential importance of melatonin

The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system. This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively. The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces. Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin. Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia. Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.

Refractory CSF leakage following untethering surgery performed 10 months after birth for enlarging terminal myelocystocele associated with OEIS complex

Background: Terminal myelocystocele (TMC) is an occult spinal dysraphism characterized by cystic dilatation of the terminal spinal cord in the shape of a trumpet (myelocystocele) filled with cerebrospinal fluid (CSF), which herniates into the extraspinal subcutaneous region. The extraspinal CSF-filled portion of the TMC, consisting of the myelocystocele and the surrounding subarachnoid space, may progressively enlarge, leading to neurological deterioration, and early untethering surgery is recommended. Case Description: We report a case of a patient with TMC associated with OEIS complex consisting of omphalocele (O), exstrophy of the cloaca (E), imperforate anus (I), and spinal deformity (S). The untethering surgery for TMC had to be deferred until 10 months after birth because of the delayed healing of the giant omphalocele and the respiration instability due to hypoplastic thorax and increased intra-abdominal pressure. The TMC, predominantly the surrounding subarachnoid space, enlarged during the waiting period, resulting in the expansion of the caudal part of the dural sac. Although untethering surgery for the TMC was uneventfully performed with conventional duraplasty, postoperative CSF leakage occurred, and it took three surgical interventions to repair it. External CSF drainage, reduction of the size of the caudal part of the dural sac and use of gluteus muscle flaps and collagen matrix worked together for the CSF leakage. Conclusion: Preoperative enlargement of the TMC, together with the surrounding subarachnoid space, can cause the refractory CSF leakage after untethering surgery because the expanded dural sac possibly increases its own tensile strength and impedes healing of the duraplasty. Early untethering surgery is recommended after recovery from the life-threatening conditions associated with OEIS complex.

MNG-2 Meningioma with aseptic meningitis

The patient, a woman in her seventies, visited the Department of Neurology at our hospital one month ago with transient right hemiparesis, and was referred to our department because a CT scan showed a 4cm extramedullary lesion in the left convexity. She was judged to have symptomatic epilepsy associated with the lesion and was started on antiepileptic drugs. The lesion showed low signal on T1WI, equal signal on T2WI, and homogeneous contrast on Gd contrast T1WI, suggesting a meningioma, but the surrounding left frontal lobe subarachnoid space was also contrasted, suggesting the possibility of seeding or other diseases. After that, the contrast area of the subarachnoid space increased in a short period of time, and the control of epileptic seizures was poor. Preoperative spinal fluid examination showed an elevated cell count and findings of aseptic meningitis. A left parietal craniotomy was performed to remove the extramedullary tumor as much as possible. The subarachnoid space of the left frontal lobe adjacent to the tumor was covered with extensive pale yellow apparently abscess-like tissue. The pathological diagnosis of the extramedullary tumor was angiomatous meningioma (WHO Grade 1), and the pale yellow tissue that filled the subarachnoid space was necrotic tissue containing neutrophils and no tumor component. IgG4 was positive in about 10% of the tumor. The postoperative course of the patient was good, the contrast area of the left frontal lobe subarachnoid space was reduced on MRI, aseptic meningitis was improved, and she was discharged home with no neurological deficits. The patient has been under outpatient observation for 2 years without recurrence of aseptic meningitis or appearance of contrast-enhancing lesions in the subarachnoid space. This case is thought to be a possible IgG4-related disease, and we report it with a discussion of the literature.

Nontraumatic Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is defined as blood in the subarachnoid space. Nontraumatic SAH is most commonly caused by rupture of an aneurysm located at the circle of Willis. Patients often present with acute thunderclap headache but also may lose consciousness or have focal neurologic deficits. Detection of an aneurysm, if present, and its treatment are needed urgently to prevent recurrent bleeding. Patients with nontraumatic SAH are prone to numerous complications that require preventative measures, early recognition, and treatment.

Hypothesis on the pathophysiology of syringomyelia based on analysis of phase-contrast magnetic resonance imaging of Chiari-I malformation patients

Background: Despite a number of hypotheses, our understanding of the pathophysiology of syringomyelia is still limited. The current prevailing hypothesis assumes that the piston-like movement of the cerebellar tonsils drives the cerebrospinal fluid (CSF) into the syrinx through the spinal perivascular space. However, it still needs to be verified by further experimental data. A major unexplained problem is how CSF enters and remains in the syrinx that has a higher pressure than the subarachnoid space. Methods: I analyzed phase-contrast MRI scans of 18 patients with Chiari-I malformation with syringomyelia undergoing foramen magnum decompression and 21 healthy volunteers. I analyzed the velocity waveforms of the CSF and the brain in various locations. The obtained velocity waveforms were post-processed using a technique called synchronization in situ. I compared between the preoperative data and the control data (case-control study), as well as between the preoperative and postoperative data (cohort study). Results: The syrinx shrank in 17 (94%) patients with good clinical improvement. In Chiari-I patients, the velocity of the tonsil was significantly larger than controls, but was significantly smaller than that of the CSF in the subarachnoid space, suggesting passive rather than active movement. The abnormal tonsillar movement disappeared after surgery, but the velocity waveform of the spinal subarachnoid CSF did not change. These results, contradicting the above mentioned hypothesis, required an alternative explanation. I thus hypothesized that there is a CSF channel between the fourth ventricle and the syrinx. This channel assumes one-way valve function when mildly compressed by the cyclical movement of the cerebellar tonsil. The decompression of the tonsils switches off the one-way valve, collapsing the syrinx. Conclusions: My hypothesis reasonably explained my data that clearly contradicted the existing hypothesis, and successfully addressed the above-mentioned theoretical problem. It will serve as a working hypothesis for further study of syringomyelia pathophysiology.