**1. Introduction**

*1.1. Brief Overview of Chiari Malformation, Syringomyelia and Related Disorders*

Chiari Malformation is a structural defect in the architecture of the skull and brain, particularly involving the position of the cerebellum. The cerebellum, which is a vital part of the brain responsible for regulating balance, muscle coordination, and some cognitive functions, descends abnormally below the skull's base in individuals with this condition.

**Citation:** Toader, C.; Ples, H.; Covache-Busuioc, R.-A.; Costin, H.P.; Bratu, B.-G.; Dumitrascu, D.-I.; Glavan, L.A.; Ciurea, A.V. Decoding Chiari Malformation and Syringomyelia: From Epidemiology and Genetics to Advanced Diagnosis and Management Strategies. *Brain Sci.* **2023**, *13*, 1658. https://doi.org/ 10.3390/brainsci13121658

Academic Editors: Giovanni Grasso and Woon-Man Kung

Received: 6 November 2023 Accepted: 24 November 2023 Published: 30 November 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Instead of resting entirely within the skull, a portion of the cerebellum protrudes into the upper segment of the spinal canal [1].

This protrusion can result in multiple issues. Primarily, it has the potential to exert pressure on the brainstem, a critical area of the brain responsible for basic life functions like breathing and heart rate. Additionally, this malformation can hinder the normal flow of cerebrospinal fluid (CSF). CSF is a clear, protective fluid that circulates around the brain and spinal cord, cushioning them from injury and helping to maintain the brain's chemical balance. When the flow of CSF is disrupted, it can cause a range of neurological symptoms that vary in intensity and type [2].

To understand and manage the condition better, medical professionals typically classify Chiari Malformation into distinct types. These classifications are based on the malformation's severity and the extent to which the cerebellum herniates or protrudes into the spinal canal. Each type has specific characteristics and implications for diagnosis and treatment [3].

Syringomyelia refers to a cavity filled with fluid that forms within the spinal cord tissue or the central canal. Over time, various theories have been proposed to shed light on the development of syringomyelia, especially when it results from blockages in the spinal subarachnoid space. Despite a century of dedicated experimental and clinical studies, the exact pathophysiological underpinnings of syringomyelia remain elusive [4].

A central topic of debate is the origin of the fluid within the syrinx and the mechanisms driving its formation. Dominant theories suggest that this cavity, or syrinx, is filled with cerebrospinal fluid (CSF). It is believed that a surge in pressure within the subarachnoid space pushes the CSF into the syrinx. Yet, this notion is counterintuitive because increasing external pressure on a cavity would typically compress it, not fill it. Moreover, it is puzzling how CSF could infiltrate the syrinx when the pressure within the syrinx is either higher than or equal to the surrounding CSF pressure [5].

Recent innovative research has started to shift the perspective on this medical enigma. Instead of focusing on external factors, contemporary studies have begun to consider internal spinal cord dynamics. This fresh viewpoint suggests that the cavity forms due to heightened pulse pressure within the spinal cord tissue. Additionally, the fluid inside the cavity may not be CSF as traditionally believed but could be extracellular fluid. The so-called "intramedullary pulse pressure theory" offers a novel explanation that seems to account for various aspects of syringomyelia, irrespective of what causes the related lesion in the subarachnoid space [6].

The various merits and limitations of past theories on syringomyelia have been meticulously dissected in thorough reviews by experts like Klekamp and Levine.

Tethered cord syndrome is a condition where the spinal cord becomes abnormally anchored to surrounding tissues, limiting its typical movement. This anomaly can give rise to complications, including Chiari Malformation and Syringomyelia. The syndrome is characterized by motor and sensory dysfunctions resulting from the undue tension exerted on the spinal cord due to this abnormal tethering. Traditionally, it is linked with the presence of a low-situated conus medullaris. The primary mode of treatment is surgical intervention, with outcomes varying from patient to patient. Even though tethered spinal cord syndrome is seldom diagnosed in emergency settings, emergency physicians must be vigilant and consider this condition in patients exhibiting symptoms reminiscent of cauda equina syndrome [7].

The aim of this comprehensive review is to put into perspective the classifications of Chiari malformation and related disorders, the therapy management of these pathologies and their genetic etiology. Therefore, this paper's main goal is to decipher the past, present, and future perspectives of Chiari malformation.

#### *1.2. Materials and Methods*

The search process was conducted using specific databases such as PubMed and Web of Science. Search terms used were "MRI imaging in Chiari malformations", "Syringomyelia", "Syrinx Pathologies", and "Chiari malformations type I, II, III, and IV", among others. The inclusion criteria specified articles written in English that referred to diagnostic imaging, surgical interventions, and outcomes of Chiari malformations. The initial search resulted in 369 articles, and after removing all duplicates, they were reviewed regarding their relevance, selecting 121 of them meeting our criteria.

#### 1.2.1. Tonsillar Configuration

The extent of tonsillar descent does not necessarily align with symptom severity, as a significant portion (around 30%) of patients with pronounced tonsillar descent may not display any symptoms [8]. Instead, the shape of the tonsils has been considered more indicative [9,10]. Pronounced compression results in peg-like tonsils that could further impede CSF flow. Such peg-shaped tonsils are more prevalent in patients with a herniation greater than 5 mm (85%), in contrast to those with rounded or intermediary forms [11].

1.2.2. Magnetic Resonance Imaging (MRI)—Craniocervical Junction—Dynamic Evaluation Dynamic Flow Studies

Dynamic studies play a role in evaluating CM-I symptoms and anticipating surgical outcomes. Healthy individuals exhibit CSF flow at the craniocervical junction that alternates in a cranial and caudal direction, mirroring cardiac and respiratory-induced variations in intracranial blood volume [12]. The spinal arachnoid space serves as a cushion, moderating intracranial pressure spikes [13]. Due to enhanced intracranial compliance, children exhibit quicker caudal velocities [14]. Phase contrast cine MRI has pinpointed notable variances in CSF velocity in symptomatic CM-I patients. Specifically, a heightened peak velocity at the FM and diminished overall volume motion were observed alongside flow jets displaying regions dominated by flow in a single direction or exhibiting concurrent bidirectional flow [2,15,16]. In symptomatic CM-I patients, unusual pulsatile actions of the cerebellar tonsils were noted, with post-surgical improvements in tonsillar pulsation amplitude and arachnoid space reduction [17,18].

CSF dynamic investigations aim to differentiate between symptomatic and asymptomatic CM-I patients, but research outcomes have been mixed [19,20]. However, in predicting surgical enhancements, CSF velocity patterns in CM-I patients might be pivotal [2,21–23]. Interestingly, patients who showcased normal preoperative hindbrain CSF flow had an almost five-fold increased likelihood of post-operative symptom resurgence, regardless of their tonsillar herniation extent or syringomyelia presence. In contrast, full CSF flow blockage prior to surgery correlated with sustained symptom relief [22]. Currently, dynamic studies assess craniocervical junction obstructions and can be indicative of a patient's aptness for surgery. While not universally applicable, identifying obstructed flow can help forecast favorable surgical outcomes in borderline scenarios or during follow-up evaluations in cases of symptom reemergence.
