The Filum disease and the Neuro-Cranio-vertebral syndrome: definition, clinical picture and imaging features.

Background We propose two new concepts, the Filum Disease (FD) and the Neuro-cranio-vertebral syndrome (NCVS), that group together conditions thus far considered idiopathic, such as Arnold-Chiari Syndrome Type I (ACSI), Idiopathic Syringomyelia (ISM), Idiopathic Scoliosis (IS), Basilar Impression (BI), Platybasia (PTB) Retroflexed Odontoid (RO) and Brainstem Kinking (BSK). Method We describe the symptomatology, the clinical course and the neurological signs of the new nosological entities as well as the changes visible on imaging studies in a series of 373 patients. Results Our series included 72% women with a mean age of 33.66 years; 48% of the patients had an interval from onset to diagnosis longer than 10 years and 64% had a progressive clinical course. The commonest symptoms were: headache 84%, lumbosacral pain 72%, cervical pain 72%, balance alteration 72% and paresthesias 70%. The commonest neurological signs were: altered deep tendon reflexes in upper extremities 86%, altered deep tendon reflexes in lower extremities 82%, altered plantar reflexes 73%, decreased grip strength 70%, altered sensibility to temperature 69%, altered abdominal reflexes 68%, positive Mingazzini’s test 66%, altered sensibility to touch 65% and deviation of the uvula and/or tongue 64%. The imaging features most often seen were: altered position of cerebellar tonsils 93%, low-lying Conus medullaris below the T12L1 disc 88%, idiopathic scoliosis 76%, multiple disc disease 72% and syringomyelic cavities 52%. Conclusions This is a paradigm shift that opens up new paths for research and broadens the range of therapeutics available to these patients.

In 1953, Garceau [5] defined the "filum terminale syndrome", or "cord-traction syndrome", reporting on three cases with a similar picture, that improved after sectioning of a thick and tight filum terminale, whereas Jones and Love [6] proposed in 1956 the term "tight filum terminale".
In 1976, Hoffmann [7] was using the term "tethered spinal cord" to define a similar clinical picture, associated to certain radiological criteria such as a low-lying medullary conus and a thick filum terminale.
As a result of these consecutive contributions, after many decades of indecision and difficulties, the tethered cord syndrome was finally described, as caused by an abnormal tethering of the spinal cord by a malformation that is evident on physical examination in the form of a spina bifida, while manifesting by a clinical picture of neurological sensorimotor impairments, predominantly in the lower limbs, associated with frequent deformities of the feet, cutaneous stigmata and genitourinary alterations, according to Fuchs, Lichtenstein and Yamada [3,4,8]. The prevalence of a symptomatic tethered cord associated with spina bifida occulta was 0.1% of 5499 primary school children in Turkey [9], while generally, all types of spina bifida occur in the range of 0.5-10 per 1000 live births worldwide [10]. The surgical treatment, indicated in 10-20% of cases, consists in the release of the spinal cord that is tethered by the myelo-meningovertebral malformation, via a lumbar laminectomy.
On the other hand, in a quite distinct direction of research, many authors observed an association amongst Arnold-Chiari Syndrome Type I, Idiopathic Syringomyelia and Idiopathic Scoliosis over the past decades [11][12][13][14][15][16][17][18] but no pathogenic explanation or possible causal relationship has been sufficiently accepted in order to warrant the initiation of more in-depth studies into this matter.
Finally, a third line of research, very close to our own vision, attempts to explain the pathogenesis of Idiopathic Scoliosis, Arnold-Chiari Syndrome Type I and Basilar Impression with a growth asynchrony between the spine and the spinal cord -a mechanism proposed by Roth in 1981 and1986 [19,20]. This would be causing a tethering of the spinal cord, as Porter advanced in 2001 [21,22], and an excessive and deforming growth of the anterior elements of the thoracic spine, leading to the production of scoliosis with rotation, according to a mechanism suggested by Dickson in 1984 [23]. Some recent magnetic resonance studies, particularly those carried out by Winnie Chou's team, have identified features which support these theories in IS patients [24], while others, as Milhorat in 2009, have applied these criteria for treatment [25].
Based on the arguments outlined in the doctoral thesis "Contribution to the etiology of syringomyelia" [26], the traction of the spinal cord and brain is proposed as the main mechanism involved in the etiopathogenesis of ISM, ACSI, IS and other diseases also considered idiopathic, such as Platybasia, Basilar Impression, Retroflexed Odontoid and Brainstem Kinking [27,28].
The objective of this article is to introduce the concept Neuro-Cranio-Vertebral Syndrome (NCVS) to define the set of clinical and imaging manifestations that affect the nervous system, the skull and the spine in the form of known diseases like Arnold-Chiari Syndrome Type I, Idiopathic Syringomyelia, Idiopathic Scoliosis and other anomalies like Platybasia, Basilar Impression, Retroflexed Odontoid and Brainstem Kinking. The Filum Disease is the most frequent congenital form of the Neuro-Cranio-Vertebral Syndrome.

Methods
Between the 14th of April, 2009 and 16th of December, 2015, 1285 patients with one or several of the diagnoses of Arnold-Chiari Syndrome Type I, Idiopathic Syringomyelia, Idiopathic Scoliosis, Platybasia, Basilar Impression, Brainstem Kinking, low-lying conus medullaris and related pathologies were seen at the Institut Chiari & Siringomielia & Escoliosis de Barcelona out of whom, we present the clinical and imaging features in a sample of 373 patients, selected because they presented complete data registered for the purposes of this investigation, after excluding cases with significant neurological or neurosurgical antecedents that could interfere with their clinical or imaging presentation: procedures such as suboccipital craniectomy, syringostomy, ventriculo-peritoneal shunting, instrumentation for scoliosis, discectomies, laminectomies for spinal stenosis, as well as demyelinating, inflammatory, tumorous or traumatic diseases of the central and peripheral nervous system.
Patients generally contact us after having been diagnosed with one or more of these conditions in their home country, because of their interest in our method used for the diagnosis, treatment and follow-up of the Filum Disease and Neuro-Cranio-Vertebral Syndrome, called Filum System® (FS®, presented on https://filumsystem.com/enfermedad-del-filum, https://filumsystem.com/enfermedadesimplicadas/ and https://institutchiaribcn.com) as we are the only center qualified to apply it worldwide, as a highly specialized private center holding the Research & Development (R&D) certification 1583.001. 16 Once the patients have arrived and have been registered at our center, after recording personal and family antecedents, the history focuses on a meticulous interview about possible Neuro-Cranio-Vertebral Syndrome symptoms, according to an anatomical order, followed by an exhaustive and detailed neurological examination centered on the Neuro-Cranio-Vertebral Syndrome and consisting mainly of the procedures presented in Table 1. The majority of patients send magnetic resonance imaging (MRI) series of the whole spine previous to their appointment, including at least sagittal and axial cuts, T1 as well as T2-weighted, as well as antero-posterior and lateral x-ray images of the entire spine taken in standing position. All these are scrutinized in the search for the following pathologies: 1. Occipitocervical Junction Malformations, of which the most common are: Basilar Impression with the odontoid ascending more than 5 mm over Chamberlain's line; Platybasia with an increased Boogaard's angle of more than 135°or a Welcher's basal angle of more than 140°; Retroflexed Odontoid with an inclination of the dens more than 2 mm behind the prolongation of the basilar line of Thiébaut-Wackenheim-Vrousos; Brainstem Kinking as seen in significant cases of Platybasia (Fig. 1).
Descent of Cerebellar Tonsils (DCT), defined as any descent of one or both cerebellar tonsils underneath the foramen magnum plane, represented by McRae's line. Furthermore, instead of measuring the length of the displacement in millimeters as is customary, we report it in relation to the occipitocervical bony structures reached by the tip of the lowermost tonsil, like the foramen magnum, the posterior arch of the atlas (C1) and the spinous process of the axis (C2) (Fig. 2). We also define as Impaction of Cerebellar Tonsils their contact or intimate closeness with McRae's line, that we consider to be an incipient form of Descent of the Cerebellar Tonsils, representing the equivalent of what other authors have denominated "Chiari malformation type 0".

Intramedullary Cyst (IMC), defined as an idiopathic
syringomyelic cavity of any size, shape and location, always having ruled out a tumoral, vascular or inflammatory etiology by the absence of abnormal contrast enhancement, as well as a traumatic etiology by patient's history and absence of any associated traumatic injuries on imaging. Moreover, cavities were classified according to the longitudinal extension along one or more vertebral levels ( Fig. 3). We also take into consideration the following two types of presyringomyelic lesions: a) Spinal Cord Ischemia-Edema, defined by an aspect of one or two parallel hyperintense lines within the spinal cord on T2-weighted sagittal images, usually associated with visible medullary edema (as focal hyperintensity) on T2-weighted axial images (Fig. 4) [29] and b) Central Canal Dilatation, when this one becomes visible, but without reaching the diameter of a filiform syringomyelic cavity (Fig. 5).

Deviation of the Vertebral Column (DVC) or
Idiopathic Scoliosis defined as any coronal plane disalignment resulting in scoliotic curvatures and being detectable on the standing spine x-ray, that we classify into the following three categories: mild, if it is up to 10°calculated with the Cobb method; moderate, if it measures between 10 and 40°Cobb and severe if it is greater than 40°Cobb (Fig. 6). We consider the presence of any abnormality of sagittal  We often observe as well other suggestive MRI features, for instance the Increase of the Supracerebellar Space ( Fig. 2), the Tense Spinal Cord (in sagittal cuts, Figs. 5 and 8) and Lateralized Spinal Cord (in coronal or axial cuts, Fig. 8), a visible Filum terminale internum and/or externum and finally, rotoscoliosis; however, despite being frequent, these changes have not been subject of the statistical analysis in this patient group.
Digital images that came in JPEG format were visualized with the program Preview version 8.1 (Apple, Inc. Cupertino, CA, USA), whilst the majority of them, in DICOM format, were viewed with the program OsiriX version 5.8.2 (Pixmeo SARL, Bernex, Switzerland). We performed an initial descriptive analysis of the general data (gender, age, type and duration of clinical course), dividing the variables into three main categories: clinical symptoms, clinical signs and imaging features. The variables followed in this study were analyzed looking for associations between components of the three categories mentioned above, taking into account topographical criteria. We used Pearson's chi-squared test and Kendall's test for ordinal data and Mantel-Haenszel chi-square test for stratified data, considering p < 0.05 as significance threshold. Finally, we created continuous variables by grouping symptoms and signs according to topographical criteria (Table 2) and these variables, as well as the different kinds of imaging features were analyzed together, first through comparison of the means  and Student's t-test for independent samples and then through the creation of dispersion diagrams and computing Pearson's correlation coefficient.

Results
Part Idescriptive analysis General data Among the 373 selected patients, 270 were females (72%), with ages between 3 and 76 years (median 33, mean 33.66, standard deviation 15.87). The time interval from the appearance of the first symptoms until the establishment of the diagnosis was greater than 10 years in 177 cases (48%), between 5 and 10 years in 70 cases (19%), between 2 and 5 years in 76 cases (20%) and rarely shorter (Fig. 9).

Neurological clinical picture
The symptoms detected in more than 10% of analyzed patients and the clinical signs detected through the specific neurological examination are presented in Tables 3  and 4.
It is worthwhile to mention that there were other symptoms as well, that we observed quite frequently throughout the study, but as they had not been contemplated in the initial list, they were not assessed in the present analysis and we can only give an overall count of the presence of each one in this patient sample: photophobia in 137 cases (37%), sonophobia in 126 cases (34%), involuntary movements or fasciculations in various body parts in 57 cases (15%) and sensations of electrical current in different regions in 40 cases (11%). On the contrary, other symptoms, although included in the study from the start, were observed too rarely to be used in the actual analysis and were therefore rejected as not being specific enough for this clinical picture: loss of consciousness in 23 cases (6%), dysphonia in 20 (5%), hypersomnia in 20 (5%), abdominal pain in 24 (6%), dysesthesias in 28 (8%), tremor in 29 (8%) and atrophy of various body segments in 22 (6%). It is furthermore notable that only 14 of our patients (4%) reported sleep apnea.
Concerning the type of clinical course, it was progressive in the majority of cases (239 patients, 64%), followed by a chronic type (177 patients, representing 31%); the remaining were much less frequent (Fig. 10).

Imaging features
The Descent of the Cerebellar Tonsils (Arnold-Chiari Syndrome Type I) was present is 273 cases (73%), while other 73 cases (20%) were interpreted as Impaction of the Cerebellar Tonsils. We have found all degrees of descent in quite balanced proportions; the most frequent variant was the one with the tonsils reaching just in front of the posterior arch of the atlas (Grade 4 in Fig. 2) (75 cases, 20%) (Fig. 11).
Intramedullary Cysts (Idiopathic Syringomyelia) were detected in 194 cases (52%), while 139 cases (37%) were interpreted as Spinal Cord Ischemia-Edema and another 8 cases (2%) had only a central canal dilatation. The most frequent location was cervicothoracic with 99 cases (26%) and it is worth noting that a cervical syringomyelia with or without variable extension in other vertebral segments was present in 135 cases (36%). As to the longitudinal extension of the syringomyelic cavity, most frequently it was over 10 vertebral segments (66 cases, 18%) (Fig. 12).
The position of the tip of the conus medullaris compared to the vertebral levels was very variable; the most frequent one was at the height of the L1L2 disc, found in 87 cases (23%) (Fig. 14).
Finally, a total of 267 cases (72%) were labeled as Multiple-level Disc Disease.

Part IIbivariate analysis
The following statistically significant associations (p < 0.05) have been found:   Moreover, through Mantel-Haenszel stratified analysis, it results that the positive relationship between the Descent of cerebellar tonsils and the Low-lying conus medullaris only exists in cases with moderate and severe scoliosis. It is also interesting that although seemingly there is no relationship between Descent of cerebellar tonsils and Intramedullary cyst when the latter includes It is worth mentioning that in all syringomyelias (intramedullary cysts), as well as if one considers only those with cervical component, there are less general and cranial symptoms than in patients without intramedullary cysts (they are negatively associated).
Concerning the Pearson correlation coefficient applied to the same new continuous variables, we observed good correlations within the group of clinical symptoms and signsthe strongest ones being between General symptoms -Cranial symptoms (r = 0.531, p = 0.000), Medullary symptoms -Medullary signs (r = 0.523, p = 0.000), Cervical symptoms -Medullary symptoms (r = 0.513, p = 0.000), Cranial symptoms -Medullary symptoms (r = 0.420, p = 0.000) and General symptoms -Medullary symptoms (r = 0.414, p = 0.000). There are statistically significant positive correlations (p < 0.05), nevertheless weaker (r between 0.106-0.149), between Cranial symptoms -Descent of cerebellar tonsils, Cranial signs -Descent of cerebellar tonsils, Cervical symptoms -Intramedullary cysts and Medullary symptoms -Intramedullary cysts. Similarly, there are weak statistically significant negative correlations (p < 0.05, r between 0.120-0.197) between General symptoms -Deviation of the vertebral column, General symptoms -Intramedullary cysts, Cranial symptoms -Intramedullary cysts, Medullary symptoms -Descent of cerebellar tonsils and Cranial signs -Intramedullary cysts. Generally, it is noteworthy that Descent of cerebellar tonsils has positive correlations with cranial symptoms and signs, while the second main image abnormality, Intramedullary cysts, has positive correlations with cervical symptoms and medullary signs.

Discussion
Historically, the mentioned pathologies have been defined in general with one or two publications, like Fuchs in 1910 [3] and Lichtenstein in 1940 [4] for the tethered cord syndrome; Hoffman in 1976 [7] for occult tethered cord and Garceau in 1953 [5], for the cord-traction syndrome and filum terminale syndrome. In none of the above was any correlation demonstrated between Idiopathic Syringomyelia, Arnold-Chiari Syndrome Type I, Idiopathic Scoliosis, Platybasia, Basilar Impression, Retroflexed Odontoid, Brainstem Kinking and a disharmonic growth conflict between the neural axis and spine, with the retention of an apparently normal filum terminale on imaging. None of these diseases has ever been related with this pathogenic mechanism, with the exception of the doctoral thesis "Contribution to the etiology of idiopathic syringomyelia" [26] in 1992, where, given the statistical evidence of a low position of the conus medullaris in Idiopathic Syringomyelia patients, has been postulated the existence of an axial caudal force affecting all of the human nervous system.
In our publications of 1996 [27,28], the apparently normal Filum terminale, i.e. not showing any abnormality on imaging, is considered the transmitter or causative agent of the traction of the spinal cord and entire central nervous system, affecting them both and their bony surroundings -skull and spine, thus being the common cause of Arnold-Chiari Syndrome Type I, Idiopathic Syringomyelia, Idiopathic Scoliosis, Platybasia, Basilar Impression, Retroflexed Odontoid and Brainstem Kinking. We call "Neuro-Cranio-Vertebral Syndrome" the presence of one or more of these diseases in a patient, and when it is impossible to identify a traumatic, tumoral, infectious, obvious malformative congenital or any other cause, we call it "Filum Disease". Roth, in 1981 and1986 [19, 20], proposed the disharmonic growth between the spine and the spinal cord to explain scoliosis and the Arnold-Chiari Syndrome I without any neurovertebral malformation. We regard   Filum Disease can manifest itself, it would not be too adventurous to believe that there are signs on imaging and symptoms and signs in the clinical picture, in the majority of humans, usually unnoticed, that could confirm the possible universal existence of a mechanical conflict between the neuroaxis and the spine.
We are aware that patient selection depends on a previous diagnosis of certain conditions, initiated by health care professionals independent of our center, as well as on the patients' assimilation of these diagnoses and of their proposed surgical solution or lack of therapeutic proposal. Although several factors can interfere in producing a selection bias (intensity of the clinical picture, individual temperamental and character features, regional cultural habits, ease of Internet use, social status, etc.) we can assume that even this search for a second  opinion, as well as their understanding of the obvious limits of the current treatment, define the patients affected by this condition and therefore should not discourage any researcher trying to explain this clinical and imaging picture. Our patient sample's representability for all population suffering with these conditions is not worrisome if one considers that it is merely the first description of a new pathology, awaiting future studies in which this global population should be better characterized in more objective conditions.

Based on the results in 373 cases Epidemiology
There is a predominance of the female gender (72%), the most frequent age to be diagnosed is 33 years (average 33.66 years, with standard deviation 15.87 years) and the time interval lapsed from onset until diagnosis is most often longer than 10 years, in 48% of cases.
Significantly, the statistical analysis confirms the presence of correlations between Conus Medullaris level and Descent of cerebellar tonsils (p = 0.008) and between Conus Medullaris level and Deviation of the vertebral column (p = 0.045). It also confirms the existence of a correlation between Descent of cerebellar tonsils and Syringomyelia with cervical component (p = 0.003), coexisting with an interestingly inverse -that is, negative -association between Descent of cerebellar and "low" Syringomyelia (without cervical component, i.e. thoracic or thoracolumbar) (p = 0.001). We also detected a positive correlation between Descent of cerebellar tonsils and Deviation of the vertebral column (p = 0.014).
Out of all symptoms and clinical signs, only the unilaterally or bilaterally positive straight leg-raising test (p = 0.048) and the unilaterally or bilaterally decreased grip strength (Kendall p = 0.019) have correlations with the level of conus medullaris. Altered deep tendon reflexes have correlations with Syringomyelia with cervical component (p = 0.005) and with Deviation of the vertebral column (p = 0.000).

Conclusion
These observations are compatible with the conclusions of the thesis: the caudal traction force applied to the nervous system by means of the filum terminale is expressed in the form of Descent of cerebellar tonsils as the entire encephalon, including its lowermost part, the cerebellar tonsils, shift through the foramen magnum; the spine, seeking to minimize trauma on the spinal cord, bends and creates abnormal spinal curvatures such as scoliosis, kyphosis, hyperlordosis, rotoscoliosis, straightening; the central spinal cord tissue suffers ischemia and necrosis with production of a cavity filled with interstitial fluid or serum, the syringomyelic cavity; by acting on the skull and brainstem at the beginning of bone maturation, Platybasia, Basilar Impression, Retroflexed Odontoid and Brainstem Kinking develop. The course of the syringomyelic cavity is toward fistulization and mixing of the intracavitary fluid with cerebrospinal fluid, towards redilatation when there is a valvular mechanism or toward collapse and spinal cord atrophy.
Concluding a doctoral thesis and resulting published papers [26-28, 31, 32], we have proceeded thus to the description of a new nosological and etiopathogenic concept, proposing the pathological conditions of Filum Disease, when its origin is congenital, and Neuro-Cranio-Vertebral Syndrome, when the nature of the mechanical conflict between neuraxis and spine is acquired.
It is important for future studies to help understand better the origin of the axial caudal force, in order to assess the impact of the Filum Disease in the individual and in the population in general, which will help to comprehend the magnitude, consequences and anomalies of the asynchronic growth between neuraxis and spine on the central nervous system, skull and spine, as well as the rest of the organism. This knowledge would allow a new line of surgical and genetic treatments of these diseases. In the field of biology, it may be of interest to determine the presence of Filum Disease in other species belonging to the mammalia class, and also its absence in non-mammalian vertebrates.
The most relevant practical corollary of this paradigm shift is the solution that we propose in order to correct or prevent these abnormalities as soon as possible, consisting of the surgical intervention of Filum terminale sectioning. This is a minimally invasive procedure aimed at the release of this fibrous structure right above its coccygeal insertion, as it has been performed in most of the patients included in this report, as an alternative to many higher-risk and challenging surgical techniques tailored to solve these conditions [31,32]. Of course, as they stand well out of the diagnostic and nosological purpose of this paper, these therapeutic innovations will be the subject of a future publication.