DOI: https://doi.org/10.21203/rs.3.rs-1675983/v1
There has recently been a trend to associate Ehlers-Danlos syndrome with vertebral instability, especially cranio-cervical instability, believed to cause clinical and imaging changes that justify extensive cranio-cervical fusion. We propose a different line of argument, in which the relationship between the spinal manifestations and the clinical picture is based on distinct phenomena, mainly an abnormal caudal traction of the central nervous system and related structures.
We conducted a retrospective study from the clinical records in our institution between 2015 and 2019 and selected 10 patients with a diagnosis of Ehlers-Danlos syndrome and neuro-cranio-vertebral syndrome. We presented their images, signs and symptoms, and compared them to those seen in 373 patients with only neuro-cranio-vertebral syndrome. From the 10 patients with Ehlers-Danlos syndrome, we report the postsurgical findings of 4 patients that underwent sectioning of the filum terminale, including significant amelioration in signs and symptoms (p < 0.05).
We found that patients with Ehlers-Danlos syndrome have more cranial and vertebral symptoms than patients with neuro-cranio-vertebral syndrome. There were also significant differences in the signs present in Ehlers-Danlos syndrome compared to those in neuro-cranio-vertebral syndrome. The patients that underwent sectioning of the filum terminale experienced significant improvements in signs and symptoms.
In patients with Ehlers-Danlos syndrome, the diagnosis of multiple cranio-vertebral or neurological manifestations must trigger a search for clinical and imaging characteristics that suggest an anomalous caudal traction, that is, a neuro-cranio-vertebral syndrome, in parallel with the tests that would help to confirm cranio-cervical instability. The probable surgical treatment would be the sectioning of the Filum terminale and cervical fusion would not at all be justified.
Ehlers-Danlos syndrome (EDS) is a complex group of inherited connective tissue disorders characterized by different degrees of joint hypermobility, excessive bruising, fragility and extensibility of the skin (1).
Due to the affectation of the connective tissue, joint hypermobility and instability is common in these patients, including in the spinal joints. Thus, atlantooccipital and atlantoaxial instability is a potential complication in this disease. Neurological examination of these patients shows sensitivity in the C1 and C2 spinous processes, alteration in the mechanics of neck rotation, hyperreflexia, dysdiadochokinesia, and hypoaesthesia (2).
The results from the bibliographic search of EDS associated with cervical pathology are scarce, as are the publications on vertebral instability (2–7). Furthermore, two cases of atlantoaxial dislocation have been found (8, 9) and one case of C1-2 dislocation associated with os odontoideum (10).
Nevertheless, Milhorat et al. (11) was the first to identify hereditary disorders of connective tissue (HDCT) associated with Arnold-Chiari I syndrome in 357 patients. He concluded: “In this report, we described a previously unrecognized association of CM-I [Chiari Malformation Type I] and HDCT [hereditary disorders of connective tissue]. We found that patients with the combined disorder exhibit varying degrees of occipitoatlantoaxial hypermobility that results in functional cranial settling, caudal displacement of the cerebellar tonsils, retroodontoid pannus formation, and symptoms referable to basilar impression”. None of these cases are known to have been operated on for cervical instability.
However, there is a clear tendency in current clinical practice to consider EDS as a frequent cause of cervical dislocation with a consequential neurological risk. Hence, surgical treatments of arthrodesis consolidation of the cervical spine are indicated with a large osteosynthesis deployment (12, 2).
In this article, the possible relationship between EDS and Neuro-cranio-vertebral syndrome (NCVS) is discussed. The NCVS was defined in a previous study as the set of clinical and imaging manifestations that affect the nervous system, skull, and spine because of a mechanical conflict between the nervous system, the spine and the Filum terminale (13). NCVS can manifest itself in various forms of diseases known as Arnold-Chiari Syndrome Type I, idiopathic Syringomyelia, idiopathic Scoliosis, and other abnormalities such as Platybasia, Basilar Impression, Retroflexed Odontoid and Brainstem kinking. While in some cases the aetiology of an acquired NCVS can be detected in the patient's medical history, in most cases, the anomalies are congenital and result in Filum disease, the most frequent form of NCVS.
The purpose of this publication is fourfold. First, to carry out a retrospective study of the clinical manifestations and imaging characteristics found in patients with NCVS associated with EDS and to compare them with a control group of 373 patients affected by NCVS, those of which are described in another article (13). Second, to propose an aetiopathogenic mechanism for NCVS in EDS patients. Third, to analyse and assess the postoperative changes of patients with NCVS associated with EDS after undergoing Sectioning of the Filum terminale (SFT). Fourth, to highlight the presence of psychological panic status, (the cervical dislocation panic syndrome), which affects some patients.
In a retrospective search of the clinical records of our institution between May 18, 2015 and December 2, 2019, 11 patients were diagnosed with EDS, in addition to NCVS. This represented 0.8% of the 1285 patients seen with diagnoses of Arnold-Chiari syndrome type I, idiopathic Syringomyelia and Scoliosis, Platybasia, Basilar Impression, Kinking of the brainstem, low-lying conus medullaris and related pathologies. After excluding one case lacking complete radiological tests, we present the clinical and imaging characteristics of 10 patients with EDS and NCVS, comparing them with the 373 patients with NCVS in a previous study on Filum disease (FD) and NCVS (13).
The selection of patients for initial visits in our institution and their diagnostic management have been presented (13). Likewise, the collection of data for the clinical manifestations (symptoms, signs, and imaging) followed similar guidelines, though there are some appreciable differences. This time, some new symptoms such as photophobia, sonophobia, sensations of electric current and involuntary movements or fasciculations, are included in the study. More clinical signs have been recorded, which were previously ruled out due to their low frequency, such as: anisocoria, inverted Lasègue test, Barré test, pain upon paravertebral pressure and in the lower extremities, scoliotic attitude, gait alteration, and quadriceps paresis test. The Jamar dynamometer was used to measure handgrip strength, instead of the Collins dynamometer.
The assessment of the MRI and X-ray images of the entire spine was done according to the same scales as in the aforementioned publication, and as depicted in Table 1.
| Conus medullaris level | Magnitude of the descent of the cerebellar tonsils | Idiopathic scoliosis |
|---|---|---|
| 1- TH12-L1 | 1- Superior third of FM-C1 | 1 - Mild |
| 2- Upper third of L1 | 2- Middle third of FM-C1 | 2 - Moderate |
| 3– Middle third of L1 | 3- Lower third of FM-C1 | 3 - Severe |
| 4– Lower third of L1 | 4- Between upper and lower edge of C1 | |
| 5- L1-L2 | 5- Lower than C1 | |
| 6- Upper third of L2 | ||
| 7– Middle third of L2 | ||
| 8– Lower third of L2 | ||
| 9- Lower than the lowest edge of L2. |
Among the 10 selected patients, 6 patients underwent SFT. 2 of these 6 patients were excluded from the study for not undergoing postoperative follow-up. Thus, we have been able to analyse the results in 4 cases at several postoperative intervals. The subjective postoperative outcome was assessed by having the patient rate his/her symptomatic evolution as a percentage of improvement or worsening, and indicate the degree of usefulness of the SFT by specifying whether it was very useful, useful, a little useful, useless, or harmful. The physician evaluated the findings of the most relevant signs and symptoms and compared them to the pre-SFT signs and symptoms. This is described in Table 2.
For data analysis, general data, clinical symptoms, clinical signs and imaging features of all patients were collected, according to a table designed in a digital format database (FileMaker Pro Advanced 11.0v2, FileMaker, Inc. Santa Clara, CA, USA), from which they were transferred to a Microsoft Excel 2011 spread sheet for Mac version 14.1.0 (Microsoft Corporation, Redmond, WA, USA) and then to a database of SPSS version 21 data (IBM Corporation, Armonk, NY, USA). The statistical significance of the differences was verified with the t test for independent samples (p < 0.05).
In the group of 10 patients with NCVS-EDS, 3 separate categories are described, and each category is represented by the patients detailed below. Patients 1, 2 and 10 are patients of more advanced age that have undergone surgery. Patients 4, 5, 6 and 7 are middle-aged and half of them have undergone surgery. Patients 3, 8 and 9 are the youngest, all with cervical hypermobility and none were operated.
Patient 1
60-year-old female with a history of multiple surgical procedures, reported parietal and frontal headache, nausea and vomiting, blurred vision, photophobia, scotoma, sonophobia, tinnitus, dizziness, mixed dysphagia, cognitive impairment (speech, concentration and memory disturbances), mood swings (nervousness, irritability, apathy and depression), general tiredness. She also reported cervical pain radiating to the shoulders and upper extremities, numbness, paraesthesia and a sensation of loss of strength in the upper extremities, upper back pain with blockage episodes, pain in the sternal region, dyspnoea, lower back pain, pain and lack of strength in the lower extremities, and impaired gait.
The physical examination detected a scoliotic attitude, pain with pressure applied to the cervical region and a bilaterally positive quadriceps paresis test, tactile hypoaesthesia in the head, upper extremities and foot soles, decreased deep tendon reflexes in upper extremities and mixed in lower extremities, slow abdominal and plantar reflexes, and a positive Romberg test.
Magnetic resonance imaging showed a slight descent of the cerebellar tonsils, multiple diseased discs and conus medullaris at the level of the middle third of the L1 vertebra. The X-ray images of the entire spine revealed a mild dextroconvex thoraco-lumbar scoliosis with 5º Cobb angle. The imaging of patient 1 is illustrated in Fig. 1.
Figure 1. Imaging of patient 1. Mild descent of the cerebellar tonsils, multiple disc disease, straightening of the cervical spine, conus medullaris at the middle third of L1, and mild deviation of the vertebral column.
Sectioning of the Filum terminale, with postoperative evaluation 52 days after surgery Improvement/disappearance of almost all the mentioned symptoms, except: the sensation of numbness, paraesthesia, sensation of loss of strength in the upper extremities, and lower back pain. On physical examination, cervicalgia and quadriceps paresis had disappeared, and tactile hypoaesthesia, Romberg test and deep tendon reflexes had partially improved.
Patient 2
64-year-old female with a medical history of suboccipital craniectomy. She reported headaches, nausea, vomiting, dizziness, dysphagia, blurred and double vision, sonophobia, speech, memory and attention disturbances, depressive state, and onset of insomnia. Also, cervicalgia radiating to the back, pain, numbness, tingling and paraesthesia in the upper extremities, dropping objects from her grip, upper and lower back pain, burning sensation, pain and paraesthesia in the lower extremities, urinary and faecal incontinence, loss of genital and anal sensation, constipation, and gait difficulties, with falls.
The physical examination revealed nystagmus, low left soft palate, pain with pressure on cervical and thoracic region, and lower extremities. Tactile and thermal hypoaesthesia and hyperaesthesia. Altered deep tendon reflexes, absence of abdominal reflexes and flexor tendency in plantar reflexes, and gait difficulty.
The MRI showed descent of the cerebellar tonsils, increased supracerebral space, and micro lacunae in the bilateral white matter and the left basal ganglia. Upper cervical kyphosis and straightening in the lower levels. Surgical arthrodesis at C4-C5 and C5-C6. Cervical, thoracic and lumbar protrusions. Ischemia and oedema in the cervical and thoracic spinal cord. Slight cervical rotoscoliosis. Disc protrusions: T7-8, T11-L1, L2-L3-L4 and disc herniation L4-L5. Loss of the lumbar lordosis. Conus medullaris at the level of the middle third of the L1 vertebra. The x-ray images of the entire spine showed levoconvex thoracolumbar scoliosis of 21º. Dysmetria of the lower extremities with shortening of the right lower extremity by 10 mm with respect to the level of the hip and 99 mm at the level of the iliac crests. 16º cervical lordosis, 49º thoracic kyphosis, 59º lumbar lordosis. The imaging of patient 2 is illustrated in Fig. 2.
Figure 2. Imaging of patient 2. Image suggestive of medullar ischemia. Impaction of the cerebellar tonsils, straightening of the cervical spine. Straightening of the upper part of the lumbar spine, conus medullaris in the upper third of L1. Brain MRI with micro lacunae in the white matter.
Improvement/disappearance of almost all the mentioned symptoms, except nausea, mixed dysphagia, speech disturbance, insomnia, pain and paraesthesia in the lower extremities, urinary and faecal incontinence, loss of genital and anal sensitivity and constipation. On physical examination, nystagmus, pain upon pressure on tender points (cervical and thoracic region, and lower legs), hypoaesthesia and hyperaesthesia to touch, and gait difficulty had disappeared. Tactile hypoaesthesia had partially improved. The other signs remained unchanged: soft palate, thermal hyperaesthesia, altered deep tendon, abdominal and plantar reflexes.
Patient 3
A 35-year-old female with multiple medical-surgical antecedents, among which the diagnoses cranio-cervical and atlantoaxial instability stand out, as well as fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity. She complains of periocular and occipital headache, with relief in decubitus, paraesthesia, itching and tension in the face, absence seizures, nausea, vomiting, subjective vertigo, dysphagia, blurred vision with black dots, feeling of pressure in the ears and temporary hearing loss, tinnitus, cognitive impairment (impaired speech, memory and attention), irritability, mixed insomnia and possible apnoea. She also reported suffering from cervicalgia, paraesthesia and lack of strength in all extremities, lower back pain, urinary incontinence, diarrhoea, constipation, lack of ability to walk, global hyperhidrosis, cold body and lack of sensation to temperature.
The objective examination detected descent of the left soft palate, decreased grip strength in the right hand, brisk deep tendon reflexes, absent left abdominal reflexes, slow plantar reflexes, extensive alterations in thermal and tactile sensitivity, positive Mingazzini and Barré tests, orthostatism and gait were impossible.
The cranio-vertebral magnetic resonance showed empty sella turcica, discrete descent of the cerebellar tonsils, C4-C5-C6 disc protrusions and cervical hypermobility with a tense medullary aspect in flexion in the incorporated dynamic test, the conus medullaris at the height of the TH12-L1 disc (Fig. 3). No scoliosis on full spine x-rays. The patient was not operated on. Cases 8 and 9 are very similar and previously diagnosed with cranio-cervical and atlantoaxial instability. The patient uses a cervical collar as she is afraid that she might suffer spontaneous cervical luxation.
Figure 3. Imaging of patient 3. Empty sella turcica, discrete descent of the cerebellar tonsils. C4-C5-C6 protrusions and tense spinal cord in cervical flexion.
Patient 4
46-year-old female with various traumatic antecedents, diagnosed with fibromyalgia and cranio-cervical and atlantoaxial instability, reported: headache, feeling of heaviness of the head, nausea, vomiting, instability, orthostatic intolerance, objective vertigo, mixed dysphagia, dysphonia, aphonia, blurred vision, photophobia, sonophobia, hearing loss, impaired speech, memory, and attention. Maintenance insomnia, general tiredness, and muscle spasms. Cervicalgia, hypermobile shoulders, feelings of tension, pain, paresis, and paraesthesia in the upper extremities. Back pain, stiffness, palpitations in orthostatism. Lower back pain, pain and numbness in the sacral area, paraesthesia, and numbness in the lower extremities. Incontinence, urinary urgency, and constipation. Gait limited by intolerance of orthostatism.
The physical examination revealed: anisocoria, deeper waist fold on both sides, quadriceps paresis, and pain upon pressure in the calf. Hyperaesthesia to temperature and hypoaesthesia to temperature and touch. Alteration of the deep tendon reflexes, abdominal reflexes were abolished, and the plantar reflexes had flexor tendency.
The MRI shows descent of the cerebellar tonsils, increased supracerebral space and postsurgical repercussions of the sphenoid sinus in the right half. Empty sella turcica. Micro lacunae bilaterally in hemispheres, basal ganglia and white matter. Straightening of the cervical spine. Cervical spinal cord with tense aspect and inferior lateral displacement, the thoracic portion appears tense with slight ischemia and oedema. Protrusions: C3-C4, C5-C6-C7, T7-T8 and L3-S1. Lumbar hyperlordosis. Sacrococcygeal hyperkyphosis. Ischemia and oedema in epiconus. Low conus medullaris at the level of the upper third of L2 vertebral body. Tarlov cyst at S2 (left). Proximal filum terminale externum visible. Levoconvex lumbar scoliosis on the spine x-ray estimated at 6º, dextroconvex cervical and thoracic scoliosis estimated at 4º. The imaging of patient 4 is illustrated in Fig. 4.
Figure 4. Imaging of patient 4. Cranial MRI with visible descent of the cerebellar tonsils in the foramen magnum, cervical MRI with straightening of the cervical spine, cervical multiple disc disease. Lumbar MRI with conus medullaris at the upper third of L2.
Patient 5
46-year-old female with a medical history of multiple surgeries, reported to suffer from occipital headache radiated to retroocular and left hemicrania, nausea and vomiting, blurred vision, sonophobia, tinnitus, plugged ears, hearing loss, vertigo, dysphagia, insomnia, nervousness, cervical pain, paraesthesia and lack of strength in the upper extremities, back pain that made breathing difficult, lower back pain, fasciculations, paraesthesia, urinary urgency and incontinence, and lack of strength in the lower extremities, with falls due to loss of coordination.
The physical examination detected spontaneous nystagmus, scoliotic attitude, thermal hypoaesthesia in the lower extremities and very extensive tactile hypoaesthesia, slight alterations of the tendon reflexes, cutaneous-plantar reflexes with a tendency to extension, diminished cutaneous-abdominal reflexes and positive Romberg test.
Magnetic resonance imaging showed moderate descent of the cerebellar tonsils, mild multiple disc disease and a low-lying conus medullaris at the level of the upper third of the L2 vertebra. The full spine x-ray ruled out scoliosis. Imaging of patient 5 is illustrated in Fig. 5.
Figure 5. Imaging of patient 5. Moderate descent of the cerebellar tonsils, conus medullaris in upper third of L2.
Improvement or disappearance of most of the mentioned symptoms, except for retroocular and left hemicranial pain, nausea and vomiting, blurred vision, back pain with dyspnoea, and hearing loss. In the physical examination, almost all the signs detected in the preoperative period improved or disappeared, except for the alterations in the osteo-tendon reflexes.
Patient 6
A 44-year-old female with various traumatic antecedents and atlantoaxial instability reported: headache from the age of 2, diplopia, blurred vision, scintillating scotoma, intense pain in the cheeks, especially when it is cold. Nausea, subjective vertigo, feeling that the throat tightens, dysphonia, photophobia and sonophobia, tinnitus, hyperosmia, impaired concentration, irritable mood, very depressed and maintenance insomnia. Intolerance to cold, overall sensation of fatigue, cervicalgia with stiffness, pain, tingling, a feeling of heaviness and paresis in the upper extremities. Back pain, intercostal pain and stiffness, blockage of breathing, pain in the lumbo-sacral area and lower extremities with paresis. Very cold feet with a tingling sensation, involuntary movements of the lower extremities, pollakiuria, nocturia, constipation, difficult gait (always accompanied). Spinal manipulations increased the pain.
The following stood out in the physical examination: uvula deviated towards the right, asymmetric soft palate, bilaterally deeper waist fold, quadriceps paresis and pain upon pressure in the back, neck and sacral area. Median lumbo-sacral bulge and discrete hypotrophy in the right lower leg. Hypoaesthesia and hyperaesthesia to temperature and touch. Alteration of deep tendon reflexes decreased abdominal reflexes and weak flexor tendency in the plantar reflexes.
Impaction of the cerebellar tonsils was observed in the MRI. Increased supracerebellar space, incipient descent of the cerebellar tonsils and sinuous course of the optic nerves with oedema in the sheaths. Multiple protrusions, especially C5-C6 and C7-T1, straightening of the cervical spine and a tense aspect of the cervical spinal cord. Discrete oedema in the cervical and thoracic spinal cord. The thoracic spine tends towards straightening. Low conus medullaris at the middle third of the L1 vertebra. Lumbarisation of S1 and visible filum terminale, somewhat thickened and tight. The full spine x-rays revealed dextroconvex thoracic and lumbar scoliosis with very discrete minor compensatory curves, in the upper and lower part; straightening of the cervical spine and hyperlordosis of the lumbar spine; lumbarisation of S1 and rotoscoliosis of the lumbar spine from L5 / S1 upwards (rotational subluxation). Imaging of patient 6 is portrayed in Fig. 6.
Figure 6. Imaging of patient 6. Increased supracerebellar space, impaction of the cerebellar tonsils, straightening of the cervical spine, image suggestive of medullar ischemia. Conus medullaris at the level of the middle third of the L1 body.
Patient 7
A 44-year-old female diagnosed with cranio-cervical instability, fibromyalgia, chronic fatigue, postural orthostatic tachycardia syndrome and mast cell activation syndrome reports: severe headache, burning sensation, sharp, stabbing pain in various parts of the head, sensation of retroocular pressure, nausea, instability, subjective vertigo, dysphagia with a feeling of tightening in the throat, blurred vision, photophobia and sonophobia, tinnitus, hearing loss, plugged ears. Impaired speech, memory and attention, brain fog, confusion, disorientation, sad and depressed mood, anxious, nervous, mixed insomnia, non-restorative sleep and overall fatigue. Overall involuntary movements such as myoclonus, generalised lack of sensitivity and lack of thermal sensitivity in the hands. Cervicalgia radiating to the lower back, pain and a feeling of heaviness in the shoulders and upper extremities, dropping objects from her grip. Back pain and intercostal pain that block breathing and make it difficult to breathe. Sacro-coccygeal, anal and pelvic pain; feeling of hypermobility of the coccyx and pelvis; and numbness of the genitals. Paresis, feeling of heaviness and spasms in the lower extremities. Pollakiuria, urinary incontinence and urgency, diarrhoea and constipation. Lack of coordination, difficult gait. The symptoms worsen in the winter. Patient presents panic of spontaneous cervical dislocation.
The physical examination highlighted: deviated uvula, altered deep tendon reflexes, right plantar reflexes tend to extension, and the left one is indifferent. Sensitivity to temperature: generalised hypoaesthesia, anaesthesia in one hand, and hyperaesthesia in the lower back and lower extremities. Hypoaesthesia and hyperaesthesia to touch. Pain at pressure: cervical, thoracic, lumbar regions and right lower leg. Heel walking is impossible.
The MRI shows descent of the cerebellar tonsils, 13mm pineal cyst, multiple disc protrusions in T4-T8 and T9-T10, with herniation T5-T6. Straightening of the thoracic and lumbar spine. Low conus medullaris at the upper third level of the L2 vertebra. The full spine x-rays show a mild double-curved thoracic and lumbar scoliosis (< 10ºCobb), lower extremity dysmetria with shortening of the left lower extremity estimated to be 3 mm at the level of the acetabular roofs and 7 mm at the level of the iliac crests. Dextroconvex lumbar scoliosis estimated to be 2° and levoconvex cervicothoracic scoliosis estimated to be 10° (both total, including all vertebrae). The estimated lateral curves, including all vertebral bodies in each region, are: cervical lordosis 25°, thoracic kyphosis 34°, and lumbar lordosis 53°. These findings are illustrated in Fig. 7.
Figure 7. Imaging patient 7. Descent of the cerebellar tonsils, straightening of the cervical spine with image suggestive of medullar ischemia. Straightening of the upper part of the lumbar spine, conus medullaris at the level of the upper third of L2.
Patient 8
A 38-year-old man diagnosed with cranio-cervical and atlantoaxial instability reported: headache, nausea, instability, vertigo, darkened, blurred and double vision, halos around lights, sonophobia, tinnitus, altered speech and concentration, brain fog, depressed mood, anxiety and nervousness, mixed insomnia, non-restorative sleep, feeling of overall fatigue. Cervicalgia radiating to the trapezius, inability to turn the head to the right, shoulder pain, numbness and lack of strength in one hand. Intercostal pain and breathing difficulties. Lower back pain, numbness and pain in one foot. Diarrhoea and constipation.
The physical examination had the following findings: deviation of the uvula, uneven shoulders, slight levoconvex scoliotic attitude and bulging of the right hemithorax. Hyperreflexia of the deep tendon reflexes, reduction and abolition of the abdominal reflexes, and flexor plantar reflexes.
The MRI showed: descent of the cerebellar tonsils and increase of the supracerebellar space, straightening of the cervical spine, multiple protrusions and discrete central spinal cord oedema C5-C7, mild scoliosis in the thoracic spine and somewhat tense aspect of the spinal cord. The Conus medullaris was at the level of the lower third of the L2 vertebra. Disc disease L5-S1. Tarlov cyst at S2. On the full spine x-rays, there was dysmetria of the lower extremities with shortening of the left lower extremity estimated to be 1 mm at the level of the acetabular roofs and 6 mm at the level of the iliac crests. Levoconvex lumbar scoliosis estimated at 5° and levoconvex cervicothoracic scoliosis estimated at 3° (both total, including all vertebrae). The estimated lateral curvatures, including all vertebral bodies in each region, were cervical lordosis 4º, thoracic kyphosis 32°, lumbar lordosis 40°. Imaging of patient 8 is illustrated in Fig. 8.
Figure 8. Imaging of patient 8. MRI of the posterior fossa with descent of the cerebellar tonsils. Cervical MRI with straightening of the cervical spine, C5-6-7 disc disease. Conus medullaris at the level of the lower third of L2. L5-S1 disc disease.
Postoperative evaluation was carried out remotely with a questionnaire in relation to his symptoms. As this is incomplete information, the case is not included in the assessment of operated patients. Most of the symptoms remained unchanged, except for nausea, instability, alterations in concentration and mood (depression, anxiety, and nervousness), general feeling of fatigue, breathing difficulties and numbness in the foot, which got worse. In addition, a new symptom appeared: dysphagia.
Patient 9
A 37-year-old female who underwent suboccipital craniectomy, diagnosed with fibromyalgia, postural orthostatic tachycardia syndrome and with various traumatic antecedents, reported: headache, left retroocular pain, burning sensation in the head, nausea, vomiting, instability, subjective vertigo, dysphagia, blurred vision, phosphenes, diplopia, photophobia and sonophobia, tinnitus, speech, memory and concentration problems, unstable mood, mixed insomnia, general tiredness and non-restorative sleep. Involuntary movements in the lower extremities. Cervicalgia radiating to the shoulders and interscapular region; and pain, numbness, and tingling in the upper extremities. Sensation of thoracic tightness with intercostal radiation. Lower back pain with blockages, radiating to the lower extremities, sensation of itching, burning and weakness in the legs, with falls. Mixed urinary incontinence and urgency, frequent urination, diarrhoea, and constipation. Limited gait.
The physical examination highlighted the following: anisocoria and nystagmus, pain with pressure in the thoracic region and lower right extremity, thermal and tactile hypoaesthesia. Scars sensitive to palpitation: extensive cervico-occipital scar, two lumbar scars and scars in the hypochondrium; Brisk deep tendon reflexes, abolition of abdominal reflexes, and flexor plantar reflexes. Difficult gait, especially on the heels.
The MRI shows: descent of the cerebellar tonsils, ischemic foci in the white matter of the cerebral hemispheres, and oedema in the optic nerve sheaths. Kyphosis of the cervical spine (especially C5-C6-C7). Tense aspect of the cervical spinal cord. Disc disease: C3-C4-C5-C6-C7-T1. Ischemia and cervical and thoracic oedema. Straightening and scoliosis of the thoracic spine. Lumbar lordosis straightening. Conus medullaris at the level of the middle third of L1. Postsurgical changes in L4-L5 (disc prosthesis). The full spine x-rays show cervical, thoracic and lumbar scoliosis, with a biggest curve being dextroconvex of wide radius in the thoracic and lumbar region. These findings are illustrated in Fig. 9.
Figure 9. Imaging of patient 9. MRI of the posterior fossa, descent of the cerebellar tonsils, increased supracerebellar space. Straightening of the cervical spine, suboccipital craniectomy with C1 laminectomy. Conus medullaris at the level of the middle third of L1. L4-5 disc prosthesis.
Patient 10
A 50-year-old female with a history of craniectomy and occipitocervical fusion, lumbar fusion and hypermobile type EDS reported headaches in the occipital region, radiation of headaches, episodes of loss of consciousness and facial paraesthesia. Nausea and vomiting, subjective vertigo or dizziness, blurred vision, diplopia, episode of amaurosis fugax, photophobia, sonophobia, tinnitus, hyposmia, hypogeusia, global dysphagia, bruxism, speech and concentration problems, mixed insomnia, and negative mood swings. Cervicalgia, with blockage episodes, that radiates into the shoulders and upper extremities. Paraesthesia, fasciculations, feeling of overall weakness, dropping objects, electric currents, burning and pricks in the upper extremities. Thoracic back pain, radiating into the intercostal region, breathing difficulty and paraesthesia. Lower back pain, with blockage episodes, radiating into the hips, sacral region, groin and thighs. Paraesthesia, paresis, fasciculations, sensation of electric current and weakness in the lower extremities. Difficult gait, difficulty climbing stairs, difficulty changing position and clumsiness when walking. Involuntary movements in all extremities when sleeping. Urinary retention and chronic constipation. Cold hands and feet, hyperhidrosis in the trunk and loss of sensitivity to touch and temperature.
The physical examination revealed: nystagmus, uvula with mild deviation to the left, uneven shoulders, bilateral tendency of scapula alata and deeper waist fold. Pain upon pressure in cervical, thoracic, and lumbar regions, and sacral area. Hypoaesthesia to temperature and touch. Alteration of the deep tendon and abdominal reflexes. Plantar reflexes in extension (Babinski's sign).
Magnetic resonance imaging showed macro lacunae bilaterally in the frontal white matter. Postsurgical changes from occiput to C7. Fusiform intramedullary cyst at C7, the rest of image of ischemia/oedema in the cervical and thoracic cord with foci of intramedullary cyst. Multiple Schmorl's hernias. Disc disease: T2-T3, T5-T6-T7, T10-T11-T12, L3-L4 and L5-S1. Straightening of cervical lordosis and thoracic kyphosis. Conus medullaris at level T12-L1. Lumbar laminectomy with interbody fusion and transpedicular screws L4-L5. The full spine x-rays showed slight misalignment of the spine in the anteroposterior plane and loss of the cervical lordosis and thoracic kyphosis in the sagittal plane. Imaging of patient 10 is displayed in Fig. 10.
Figure 10. Imaging of patient 10. Macro lacunae in white matter, intramedullary cyst at C7, arthrodesis C6-7, cervical straightening. Lumbar straightening, conus medullaris at T12-L1, arthrodesis L4-5.
Sectioning of Filum terminale with postoperative evaluation 8 days after surgery Improvement/disappearance of almost all the mentioned symptoms, with the exception of paresis and involuntary movements of all the extremities falling asleep, which did not change. On physical examination, the pain upon pressure (cervical, thoracic, and lumbar regions), the temperature hypoaesthesia, and the alteration of the deep tendon reflexes had disappeared, and the Babinski's sign had partially improved. The rest of the signs remained unchanged or were not assessed.
Descriptive analysis of NCVS-EDS
Among the 10 selected patients, 9 were females (90%) and 1 was male (10%). They were between 35 and 64 years old (median 45, mean 46.3, standard deviation 9.51) (Table 2).
| Patient | Sex, age | Diagnoses | SFT date | Postoperative findings | Observations | Surgical Effectiveness (patient / doctor) |
|---|---|---|---|---|---|---|
| 1 | F, 60 | NCVS, FD, EDS, DCT, MD | 19-May-14 | Improvement of most symptoms | Use of neck brace due to pain | 100% clinical improvement, very useful / 78% clinical improvement |
| 2 | F, 64 | NCVS, FD, EDS, DCT, MD | 15-Dec-15 | Improvement and disappearance of most symptoms | Increased back mobility, improved gait | 100% clinical improvement, very useful / 77% clinical improvement |
| 3 | F, 35 | NCVS, FD, EDS, DCT, MD, Cervical hypermobility | - | - | Use of neck brace due to instability, CDP | - |
| 4 | F, 46 | NCVS, FD, EDS, DCT, DS, MD, LCM | - | - | Dislocation of the fingers of the hands | - |
| 5 | F, 46 | NCVS, FD, EDS, DCT, ACSI, IS, MD | 16-Feb-17 | Improvement and disappearance of most symptoms | - | 50% clinical improvement, very useful / 74% clinical improvement |
| 6 | F, 44 | NCVS, FD, EDS, ICT, DS, LCM, MD | - | - | - | - |
| 7 | F, 43 | NCVS, FD, EDS, DCT, LCM, DS, MD | - | - | CDP | - |
| 8 | M, 38 | NCVS, FD, EDS, DCT, DS, LCM, MD | 28-May-19 | Worsening of non-pain symptoms | - | N/A, remote postoperative follow up |
| 9 | F, 37 | NCVS, FD, EDS, DCT, DS | - | - | Cervical spine with arthrodesis | - |
| 10 | F, 50 | NCVS, FD, EDS, IS, MD | 3-Sep-19 | Improvement and disappearance of most symptoms | Subsequent wound infection | 70% clinical improvement, very useful / 89% clinical improvement |
In the surgical effectiveness column, the patient evaluated his/her evolution as a percentage of subjective improvement or worsening, and the degree of usefulness of the surgery by using the scale “very useful, useful, not very useful, useless, harmful”. The doctor objectively assessed and recorded the evolution of postsurgical signs. Where: ACSI: Arnold Chiari syndrome type I; CDP: cervical dislocation panic syndrome; DCT: descent cerebellar tonsils; DS: deviated spine; EDS: Ehlers-Danlos syndrome; FD: filum disease; ICT: impaction of cerebellar tonsils; IS: idiopathic syringomyelia; LCM: low conus medullaris; MD: multiple diseased discs; NCVS: neuro-cranio-vertebral syndrome; SFT: sectioning filum terminale.
The time interval from the appearance of the first symptoms to the diagnosis was longer than 10 years in 9 cases (90%) and between 2 and 5 years in 1 case (10%).
Regarding the type of clinical course, in half of the cases (50%) it was progressive and in the other half it was chronic - it was of long duration but without any clear impression of progression over time.
It is interesting that the 10 patients share very similar medical-surgical antecedents: multiple allergies and intolerances (10/10), various components of central sensitivity syndromes (5/10), thyroid problems (5/10), regular treatment with opioid and related analgesics (8/10) and multiple surgeries for various conditions (8/10).
The clinical signs and symptoms detected in the specific neurological examination of these 10 patients are presented in Table 3 and 4 respectively.
| Symptoms | Percentage (%) |
|---|---|
| Nausea and / or vomiting | 100 |
| Balance disorders1 | 100 |
| Visual alterations2 | 100 |
| Neck pain | 100 |
| Lumbo-sacral pain | 100 |
| Chiari-type headache | 90 |
| Sonophobia | 90 |
| Altered attention | 90 |
| Cognitive impairment | 90 |
| Mood alterations | 90 |
| Insomnia | 90 |
| Pain in upper extremities | 90 |
| Gait alterations | 90 |
| Dysphagia | 80 |
| Tinnitus | 80 |
| Language disorders | 80 |
| Paraesthesia | 80 |
| Sensation of lack of strength in upper extremities | 80 |
| Sphincter alterations4 | 80 |
| Nervousness / irritability | 70 |
| Back pain | 70 |
| Sensation of lack of strength in lower extremities | 70 |
| Photophobia | 60 |
| Memory impairment | 60 |
| Sadness | 60 |
| Global tiredness | 60 |
| Pain in lower extremities | 60 |
| Diplopia | 50 |
| Numbness in upper extremities | 50 |
| Altered thermal perception3 | 50 |
| Involuntary movements / fasciculations | 50 |
| Chest pain | 40 |
| Anxiety | 20 |
| Numbness in lower extremities | 20 |
| Sensations of electric current | 20 |
| Atypical headache | 10 |
| Sensation of lack of strength upper extremities | 0 |
| 1Babinski's sign present unilaterally or bilaterally in 3 cases (30%) | |
| Signs | Percentage (%) |
|---|---|
| Altered deep tendon reflexes lower extremities | 100 |
| Altered deep tendon reflexes upper extremities | 90 |
| Altered tactile sensitivity | 90 |
| Altered cutaneous-abdominal reflexes | 80 |
| Altered cutaneous-plantar reflexes1 | 80 |
| Altered thermal sensitivity | 80 |
| Sensitivity to paravertebral pressure and lower extremities | 80 |
| Romberg test | 70 |
| Decreased grip strength | 60 |
| Scoliotic attitude | 60 |
| Inverted Lasègue manoeuvre | 50 |
| Nystagmus | 40 |
| Uvula deviated | 40 |
| Lasègue manoeuvre | 30 |
| Barré manoeuvre | 30 |
| Positive tests for paresis | 30 |
| Toes / heels gait disturbance | 30 |
| Quadriceps paresis test | 30 |
| Anisocoria | 20 |
| Mingazzini manoeuvre | 20 |
| 1Instability, dizziness, vertigo, etc. 2Blurred vision, phosphenes, scotoma, etc. 3Sensation of cold hands and/or feet, intolerance/insensitivity to cold/ heat. 4Pollakiuria, enuresis, incontinence/retention, urgency, etc. | |
The descent of the cerebellar tonsils (Arnold-Chiari Syndrome type I) was present in 8 cases (80%), the majority (50%) were mild (upper/middle third of the O-C1 interval), and in one case (10%), there was only an impaction of the cerebellar tonsils. The descriptive summary of imaging results in the 10 patients with NCVS and EDS are presented in Table 5.
| Conus medullaris level | Descent of cerebellar tonsils magnitude | Idiopathic scoliosis | |
|---|---|---|---|
| Patient 1 | 3 | 1 | 1 |
| Patient 2 | 2 | 3 | 2 |
| Patient 3 | 1 | 1 | 0 |
| Patient 4 | 6 | 1 | 1 |
| Patient 5 | 6 | 3 | 0 |
| Patient 6 | 7 | 0 | 1 |
| Patient 7 | 6 | 2 | 1 |
| Patient 8 | 8 | 2 | 1 |
| Patient 9 | 3 | 3 | 1 |
| Patient 10 | 1 | 0 | 1 |
| For numerical key, see Table 1. | |||
Spine deviation (idiopathic scoliosis) was observed in 8 cases (80%). In the majority (70%) of the cases it was mild (up to 10º Cobb), while in one patient (10%) it was moderate (between 10º-40º Cobb).
We only found an intramedullary cyst (idiopathic syringomyelia) in case number 5 but nevertheless, in all the other cases, areas interpreted as spinal cord ischemia-oedema have been observed.
The position of the tip of the conus medullaris with respect to the vertebral levels was highly variable. The most frequent conus medullaris level was at the upper third level of the L2 vertebra, in 3 cases (30%).
Regarding malformations of the occipito-cervical junction, in this series we have not found any case with Retroflexed Odontoid, Basilar impression, Platybasia or Brainstem kinking.
Comparison between the 10 patients with NCVS-EDS and the 373 cases with NCVS-FD.
The symptomatic comparison between the 10 patients with NCVS associated with EDS and the group of 373 cases with NCVS published by Royo-Salvador et al. (13) is represented in charts that divide the symptoms into two large categories: cranial (Fig. 11), and vertebral (Fig. 12). The comparison regarding the physical examination is represented in Fig. 13. Only the variables present in both studies have been considered when presenting this data. To compare the imaging features, we have graphically represented the descent of the cerebellar tonsils level in Fig. 14, the degree of the deviation of the spine in Fig. 15, and the conus medullaris level in Fig. 16.
Figure 11. Comparison of cranial symptoms between 10 patients with SNCV-EDS and 373 patients with NCVS (13).
Figure 12. Comparison of vertebral symptoms between 10 patients with NCVS-EDS and 373 patients with NCVS (13).
Figure 13. Comparison of clinical signs between 10 patients with NCVS-EDS and 373 patients with NCVS (13).
Figure 14. Comparison descent of cerebellar tonsils between 10 patients with NSCV-EDS and 373 patients with NCVS (13).
Figure 15. Comparison degree of spinal deviation between 10 patients with NCVS-EDS and 373 patients with NCVS (13).
Figure 16. Comparison conus medullaris level between 10 patients with NCVS-EDS and 373 patients with NCVS (13).
We found that patients with EDS are clearly distinguished within the group of individuals affected by NCVS as they have more cranial (Fig. 11) and vertebral (Fig. 12) symptoms, such as: headache, visual disturbances, tinnitus, pain in the upper extremities, neck pain, lumbo-sacral pain, sensation of lack of strength in upper extremities, nausea and/or vomiting, dysphagia, insomnia, and gait disturbances.
Regarding the signs, among those that were significantly more frequent in the EDS, we found: altered deep tendon reflexes in the lower extremities, altered tactile sensitivity and a positive Romberg test. On the other hand, signs such as nystagmus, decreased grip strength, the Lasègue and Mingazzini tests were significantly less frequent compared to the group of patients with NCVS without EDS.
There was little significant difference between the two groups regarding the MR imaging and full spine x-rays, except for an evident lack of syringomyelia in patients with NCVS and EDS.
Postoperative check-up was carried out 8 days, 7weeks, 4 months, and 14 months after the SFT. On a global level, the postoperative evolution of all neurological symptoms and signs in the 4 patients is represented respectively in two circular charts (Fig. 17A and B). The specific evolution of each symptom and sign in each patient after the SFT is shown in Table 6, 7 and 8.
Figure 17. Synthesis of the postoperative evolution in 4 patients after sectioning of the filum terminale. Evolution of symptoms in A, and evolution of signs in B.
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
|---|---|---|---|---|
| Headache | ↑ | ↑ | ↑ | ↑ |
| Balance disorders1 | ↑ | ↑ | ↑ | ↑ |
| Visual alterations2 | ↑ | ↑ | → | ↑ |
| Diplopia | ↑ | ↑ | ||
| Tinnitus | ↑ | ↑ | ↑ | |
| Language disorders | ↑ | → | ↑ | |
| Memory impairment | ↑ | ↑ | ||
| Attention alterations | ↑ | ↑ | ↑ | |
| Sadness | ↑ | ↑ | ||
| Anxiety | ||||
| Nervousness / irritability | ↑ | ↑ | ↑ | |
| Nausea and / or vomiting | ↑ | ↑ | → | ↓ |
| Dysphagia | ↑ | → | ↑ | ↑ |
| Insomnia | → | ↑ | ↑ | |
| Global tiredness | ↑ |
Where: the upward arrow is improvement or disappearance of symptoms, the rightward arrow is no change, the downward arrow is worsening. Blank spaces indicate that the symptoms are not present.
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
|---|---|---|---|---|
| Pain upper extremities | ↑ | ↑ | ↑ | |
| Pain lower extremities | ↑ | ↓ | ↑ | |
| Chest pain | ↑ | → | ↑ | |
| Neck pain | ↑ | ↑ | ↑ | |
| Upper back pain | ↑ | ↑ | ↓ | ↑ |
| Lumbosacral pain | → | ↑ | ↑ | ↑ |
| Numbness upper extremities | → | |||
| Numbness lower extremities | ||||
| Paraesthesia | → | ↑ | ↑ | ↑ |
| Altered thermal perception | ↑ | ↑ | ||
| Sensation lack of strength upper extremities | → | ↑ | ↑ | |
| Sensation lack of strength lower extremities | ↑ | ↑ | ↑ | |
| Sphincter alterations | → | ↑ | ↑ | |
| Gait alterations | ↑ | ↑ | ↑ | ↑ |
Where: the upward arrow is improvement or disappearance of symptoms, the rightward arrow is no change, the downward arrow is worsening. Blank spaces indicate that the symptoms are not present.
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
|---|---|---|---|---|
| Nystagmus | ↑ | ↑ | ↑ | |
| Uvula deviation | → | |||
| Decreased grip strength | ↑ | ↑ | ↑ | |
| Altered deep tendon reflexes upper extremities | ↑ | → | → | |
| Altered deep tendon reflexes lower extremities | → | ↓ | → | ↑ |
| Altered abdominal reflexes | → | → | ↑ | |
| Altered plantar reflexes | ↑ | → | ↑ | ↑ |
| Altered thermal sensitivity | ↑ | ↑ | ↑ | |
| Altered tactile sensitivity | ↑ | ↑ | ↑ | ↑ |
| Lasègue test | ↑ | |||
| Inverted Lasègue test | ↑ | |||
| Mingazzini test | ↑ | |||
| Barré test | ↑ | |||
| Sensitivity to paravertebral pressure and lower extremities | ↑ | ↑ | ↑ | |
| Scoliotic attitude | → | → | → | |
| Romberg test | ↑ | ↑ | ↑ | ↑ |
| Toes / heels gait disturbance | ↑ | |||
| Quadriceps paresis test | ↑ |
Where: the upward arrow is improvement or disappearance of signs, the rightward arrow is no change, the downward arrow is worsening. Blank spaces indicate that the signs are not present.
Some observations can be made about the results after SFT in these 4 patients with NCVS and EDS:
cranial symptoms that improved or disappeared: Chiari-type headache, diplopia, tinnitus, alterations in balance and mood, overall fatigue, memory, and concentration impairment (Table 6).
vertebral symptoms that improved or disappeared: pain in the upper extremities and cervical region, altered thermal perception, sensation of loss of strength in the lower extremities and gait alterations (Table 7).
clinical signs that improved or disappeared: nystagmus, decreased grip strength, alteration of thermal and tactile sensitivity, Lasègue test, inverted Lasègue test, Mingazzini test, Barré test, sensitivity pressure in paravertebral region and lower extremities, positive Romberg test, altered toe/heel walking, and quadriceps paresis test (Table 8).
The series of patients presented in this paper contribute new information to the peculiarities of the neurological clinical picture in patients with EDS. At the same time, we propose an alternate explanation for EDS: an axial intramedullary tension mechanism, which replaces the increasing trend of attributing this condition to cranio-cervical instability.
In the medical literature, the description of cervical or atlantoaxial subluxations and dislocations in patients with EDS is scarce. Moreover, most of those that have been presented so far are associated with bone malformations such as atlas hypoplasia, os odontoideum, C1 bifid vertebra and Klippel-Feil type vertebral fusion (14, 10, 15). The initiative of Halko et al. is an exception, in which 26 patients with EDS were radiologically evaluated, resulting in 2 cases (7.7%) with atlantoaxial subluxation (16). These findings are far from the 65% that represents the frequency of the same condition in rheumatoid arthritis (17).
A recent study reported that Arnold-Chiari syndrome type I is a comorbid condition in hypermobile EDS and can be complicated by craniocervical instability or Basilar Impression (2, 11). While analysing the MRI of the patients with EDS and Arnold-Chiari syndrome type I, Milhorat found a greater formation of retro-odontoid pannus, compared to patients with Arnold-Chiari syndrome type I alone. In patients with EDS, the atlanto-axoid interval that defines instability remained constant, when the parameter was incorporated. The parameters of the occipital-atlas-axis relationship were altered more than in patients with Arnold-Chiari syndrome type I (18). In another study, Eppelheimer (19) detected a lower tonsillar position in patients with EDS and Arnold-Chiari syndrome type I, compared to patients with Arnold-Chiari syndrome type I without EDS, a result consistent with our current findings.
It is interesting to observe how those that support the theory of cranio-cervical instability in EDS are adjusting their reasoning and moving closer to spinal traction theories (4, 20). They are culminating the design of an ingenious mathematical method to calculate deformative tissue stress according to movements and actions applied on the medulla oblongata and cervical spinal cord (3). The main problem with the theories that support instability mechanisms is that they do not ground themselves on neurological deficits, contrary to other pathologies of the nervous system. Patients are characterised by the almost constant nature of their symptoms that can greatly limit their physical and social activity. In addition, the vertebral instability theory only finds hypermobility-type anomalies at the extremes of movement, which the patient likely does not perform in daily life. The same can be reasoned about the theory of dynamic Basilar Impression and the consequent compression of the medulla oblongata-cervical area in patients with EDS. These arguments can also be used to make a leap toward the theory of spinal cord traction: we propose that tissue stress within the brainstem and spinal cord is abnormally high in these patients, as is the case with NCVS. This high stress is present both at rest and during head movements and changes in body position, and is conditioned by developmental anomalies in some mechanisms that we try to explain in other works (13, 21, 22, 23).
Regarding the great variety of neurological symptoms found in these patients, our data support and complement previously published information. In 2011, Rombaut et al. (24) observed that EDS patients reported numerous symptoms including pain (100%), joint problems (84.8%), and muscle pain (64.6%). There were also symptoms suggestive of dysautonomia (dizziness, nausea, vomiting, urinary retention) (58.2%), fatigue (49.4%), headaches (36.7%) and various neurological problems (paresis, paralysis and paraesthesia) (29.1%). In less frequency, patients presented insomnia, cognitive problems (memory loss, frequent errors) and speech related problems (dysphagia, vocal problems). In addition, their patients also showed a high consumption of therapeutic resources, especially analgesic medication, and suffered from severe dysfunction in daily life activities (24).
Castori and Voermans (6) also highlight the significant presence of pain, not only the chronic dominant joint pain, but also in the form of cramps, myalgias, peripheral neuropathies and visceral pain of various kinds. They found a very high prevalence of severe fatigue, in up to 84% of cases, in direct relation to age, its impact on quality of life being many times greater than that of pain. Other fatigue-related disorders are common, such as sleep disturbances, concentration problems, and symptoms of dysautonomia, often in form of orthostatic tachycardia syndrome. Headaches of various types (migraine, tension, mixed, posttraumatic), pain in the temporo-mandibular joint, cervical pain, epilepsy, lack of strength, hypotonia, limited gait, paraesthesia, and numbness of the extremities are frequent. These patients suffer from peripheral neuropathies, especially of the ulnar nerve, due to stretching, pressure or dislocation of the nerve. In fact, their peripheral nerves may be more vulnerable due to the defects in the connective tissue that makes up nerve sheaths (6).
The improvements observed in cases with cervical arthrodesis can be attributed to the association with the sectioning of the Filum terminale, which is practiced in most cases (12).
Comparison of the NCVS-EDS series with the descriptive series of NCVS/EF
It is our objective to present a retrospective study of the clinical manifestations and imaging characteristics found in patients with NCVS associated with EDS and to compare them with a control group of 373 patients affected by NCVS, that has already been presented in another article (13). The patients we present have been selected from a group of conditions whose complicated neurological picture is described in detail in a recent article (13). The selected patients are characterised by having an intense and rich symptomatologic picture, with more headaches (which is usually the typical occipital headache triggered by physical exertion and Valsalva manoeuvres), visual disturbances, tinnitus, neck pain, lower back pain, pain and lack of strength in upper extremities, nausea and/or vomiting, dysphagia, insomnia and gait disturbance.
In the objective examination, patients with NCVS-EDS show alterations comparable to the group of 373 patients with NCVS, but with significantly more alterations in the deep tendon reflexes in the lower extremities, alterations in tactile sensitivity and positive Mingazzini test.
The images do not differ much from those found in the original group, except for a very scarce association of syringomyelia. It is tempting to attribute this to the same greater elasticity of the leptomeninge under continuous cranio-caudal tissue stress, which constitutes the main postulate of our theories. And the absence of craniocervical malformations such as Basilar Impression, Platybasia, Retroflexed Odontoid, and Brainstem kinking is indicative of two possible circumstances: one is the late manifestation of the pathological mechanism that generates the NCVS and the second is the greater elasticity of the transmitting elements and spinal traction receptors.
Future studies with larger series should confirm whether the tendency of patients with EDS, compared to patients with NCVS and FD, have less descent of the cerebellar tonsils, less idiopathic scoliosis and a less low-lying Conus medullaris.
Aetiopathogenic mechanism of NCVS in EDS
Filum Disease is a pathology that triggers the appearance of most of the diseases it generates, including: Arnold-Chiari syndrome type I, idiopathic Scoliosis and idiopathic Syringomyelia, Basilar Impression, Platybasia, Retroflexed Odontoid, Brainstem kinking and others. These are the consequence of a traction of the nervous system due to the conflict between asynchronous growth between the nervous system, the spine, and the Filum terminale.
In the ninth week of gestation, if the spine grows more in relation to the spinal cord, it causes the spine to apply traction on the spinal cord as they are both united at the caudal level by the Filum terminale. Depending on the intensity of the conflict, neurological, cranial and spinal injuries appear, expressing themselves in relevant cases with multiple neurological symptoms and signs.
The NCVS is consequence of the same mechanism as the Filum Disease, but in addition to the congenital cause, other acquired causes can add to the asymmetry between the spine and the spinal cord, as is evident in the cases presented in this paper with the existence of EDS-related anomalies.
First, in the case of EDS, the generalized ligamentous laxity that affects the spine and intervertebral discs allows an elongation that does not match the spinal cord tissues. It creates a traction gradient that generates a mechanical conflict in the entire nervous system, which is impacted and anchored in the foramen magnum, and transmitted by the Filum terminale (Figs. 18 and 19.1).
Figure 18. Representation of the elongation of the spine. Increased elasticity of the spine in a case of EDS, which conditions a traction of the spinal cord with descent of the cerebellum and the cerebellar tonsils from the lower part.
Second, in normal conditions, the Filum terminale should have a flexing effect over the entire spine that contributes to the generation, together with gravity, of the physiological curves in the sagittal and coronal planes. However, these physiological curves disappear or are minimised when the Filum terminale and the vertebral symphyses are loose, hence increasing the lengthening of the spine (Fig. 19.2).
Figure 19. Factors that contribute to the elongation of the spine. In patients with EDS, elongation may be due to 1. the increased elasticity of the spine and the 2. decreased flexing effect with a lax Filum terminale. 3. Until reaching a limit where spinal traction begins.
Third, the Filum terminale, despite being slacker in EDS and allowing elongation of the spine, reaches a limit during growth, where its elastic behaviour is altered and the Filum terminale becomes increasingly stiff and tense. When this elongation process continues, it begins to exert a noticeable traction on the spinal cord, or partially decreases the intensity of the traction of the spinal cord. As this traction is slow and of low intensity, it does not present with the bony deformations of Filum Disease such as Basilar Impression, Platybasia, Retroflexed Odontoid, and idiopathic Syringomyelia occurs with less frequency. (Fig. 19.3).
A very different possibility of interpreting these findings would be that patients with EDS develop a clinical picture of a central sensitivity syndrome like fibromyalgia and chronic fatigue, as they carry multiple somatic mechanical conflicts, caused by abnormalities in the composition and biomechanical behaviour of the connective tissue. They develop these syndromes earlier and more intensely than other patients suffering from a Neuro-cranio-vertebral syndrome.
Postoperative changes in NCVS-EDS after SFT
In any case, the results of sectioning of Filum terminale surgery in patients with EDS seem to be superimposable as those of the patients with Neuro-cranio-vertebral syndrome (21, 22, 25). However, they need prospective confirmation with more cases and more regular follow-up based on validated outcome scales.
Psychological status of panic of spontaneous cervical dislocation
The history of the disease of some of the patients in this series shows the existence of a very marked panic of suddenly suffering a cervical dislocation due to a possible or confirmed Ehlers-Danlos syndrome. We have called this psychological syndrome "cervical dislocation panic syndrome" (CDP). It creates an obsessive state that is very difficult to mitigate. It can only be diminished with an important argument that discourages the probability of cervical dislocation or the practice of cervical arthrodeses, which are mostly unnecessary (12).
We have found ten cases among 373 cases of NCVS and/or Filum Disease, in which EDS may play an inductive or aetiopathogenic role. This seems to be confirmed by the clinical correlation in a comparative study with symptoms, signs and complementary examinations.
It is plausible that the greater elasticity of the tissues in EDS cause the spine to elongate and increase in length. This generates a traction of the nervous system transmitted by the spinal cord and the Filum terminale, resulting in NCVS by itself, or with an underlying Filum disease.
The elimination of the traction that the central nervous system was subjected to in the four patients affected by NCVS-EDS and operated on by means of the sectioning of the external Filum terminale, resulted in an improvement in signs and symptoms. Despite the small number of cases, sectioning of the Filum terminale seems to be a positive treatment option, and our results suggest that there is good motivation for its application.
We consider that the symptoms in cases with EDS that some authors attribute to cranio-cervical and/or atlanto-axoid instability, are not associated to this mechanism. Rather, we propose that they reflect a Neuro-cranio-vertebral syndrome that could benefit from sectioning of Filum terminale surgery. This surgery is technically much easier, and with less risk than an unjustified fusion of the entire cervical spine. Spinal fusion surgery should only be considered as a last resort, in cases where sectioning of the Filum terminale does not have a satisfactory effect and severe vertebral instability is clearly demonstrated by dynamic imaging tests of the spine.
The panic syndrome of cervical vertebral dislocation, which is usually induced, can be avoided by better communicating information to EDS patients, and indicating the absence of cervical vertebral dislocation in EDS cases. One should not confuse hypermobility of the cervical spine with the tendency to dislocate.
cervical dislocation panic syndrome
Ehlers-Danlos syndrome
filum disease
neuro-cranio-vertebral syndrome
sectioning of the filum terminale
Ethics approval and consent to participate
We used our centre’s database of patient records retrospectively. Patient data were anonymised in accordance with the legislation existing when the study was initiated, following the necessary technical and organisational guarantees and measures, and without the requirement of an ethics committee. The need for informed consent was deemed unnecessary according to the regulations established by Regulation (EU) 2016/679 Article 89.1 of the European Parliament and of the Council of 27 April 2016 (GDPR) and Organic Law 3/2018 of 5 December on the Protection of Personal Data and Guarantee of Digital Rights (LOPD). All methods were carried out in accordance with relevant guideline and regulations. No additional administrative permission was required to access the raw data in this study.
Consent for publication
Formal consent for the publication of participant data was not required, given that only anonymised data was used and followed the Regulation (EU) 2016/679 Article 89.1 of the European Parliament and of the Council of 27 April 2016 (GDPR) and Organic Law 3/2018 of 5 December on the Protection of Personal Data and Guarantee of Digital Rights (LOPD) of personal data protection. According to these regulations of personal data protection), this is sufficient, provided that a confidentiality commitment has been made and specific safety measures have been adopted.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author upon request.
Competing interests
The authors declare that they have no competing interests.
Funding
No funding was received for this research.
Authors’ contributions
Study Design: MRS.
Data Collection: MRS, MFR.
Statistical Analysis: AP.
Data interpretation: MRS, JAA.
Manuscript Preparation: MRS, JAA, MFR, AP.
Literature Search: MRS, AP.
All authors read and approved the final manuscript.
Acknowledgements
We would like to thank Mr. Juan Manuel Jené Gaspar for updating the FileMaker Pro database and assisting in image pre-processing and editing of the manuscript. Mr. Anoop Tiwari, Ms. Katharina Kühn and Ms. Pamela Villavicencio for their help in the translation and review of the manuscript. Ms. Gioia Luè for the management of the institute’s R + D + i department. Dr. Salca for his help in the study and manuscript preparation. We would also like to thank Ms. Mara Espino Hernández for her administrative, social, and financial management to the projects at Institut Chiari & Siringomielia & Escoliosis de Barcelona, Chiari & Scoliosis & Syringomyelia Foundation, Filum Academy Barcelona. We thank all the other staff at the Institut Chiari & Siringomielia & Escoliosis de Barcelona that have contributed to patient care and data collection, preparation and analysis. We thank all our patients and caregivers, without whom this work would not have been possible.