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Neurology and New Treatment Modalities in Fibromyalgia
The focus of this symposium was two-fold:
IS THERE AN ASSOCIATION BETWEEN CERVICAL MYELOPATHY AND FIBROMYALGIA? Dan Heffez, MD, et al Introduction: Cervical myelopathy and fibromyalgia have a number of symptoms in common. It has been suggested that fibromyalgia may be incorrectly diagnosed in some patients who actually have cervical myelopathy or perhaps that cervical spinal cord dysfunction is the underlying cause of the fibromyalgia syndrome. In order to examine the possible relationship between cervical myelopathy and fibromyalgia, we undertook a prospective nonrandomized, case control outcome study of operative versus non-operative treatment of cervical myelopathy in patients who had previously been diagnosed with fibromyalgia. Methods: Patients carrying the diagnosis of fibromyalgia were referred for neurological evaluation in order to exclude the possibility of myelopathy. Patients underwent a highly structured evaluation, which included a neurological examination by a neurologist and a neurosurgeon, a psychological interview and detailed neuroradiological imaging of the brain and cervical spine. The radiological evaluation included MRI of the cervical spine, MRI of the brain with the axial cuts through the plane of the foramen magnum and dynamic contrast enhanced CT of the cervical spine. Patients also completed a HADS and a SF-36 outcome questionnaire. All data was gathered prospectively and entered into a relational database. Patients were followed up every 3 months using a uniform mail-in questionnaire regardless of treatment prescribed.
Cervical myelopathy was diagnosed in the face of symptoms consistent with myelopathy and in the presence of neurological signs indicative of cervical spinal cord dysfunction. Both symptoms and signs of myelopathy were required for inclusion in the outcome study.
Results: There were 64 patients in the surgical group and 44 patients in the non-surgical group. While the patients were not randomized to the treatment arms, the 2 groups were virtually identical with regards to sex ratio, mean age, mean duration of illness, history of craniospinal trauma, level of education and work history. The prevalence of those symptoms commonly associated with both cervical myelopathy and fibromyalgia, including pain, headache, numbness, tingling, instability of gait, dizziness and grip weakness was identical in the 2 groups of patients. The prevalence of those symptoms commonly associated with fibromyalgia but not with cervical myelopathy such as fatigue, cognitive difficulties, irritable bowel syndrome, insomnia and depression did not differ between the 2 groups. The findings on neurological examination did not differ between the 2 groups. The most prevalent findings were high thoracic spinothalamic sensory level to a cold or pinprick stimulus, hyper-reflexia, recruitment of reflexes, Hoffman sign, ankle clonus and absent gag reflex. In both surgical and non-surgical patients, the pyramidal tract findings became more pathological when the patient was examined with the neck positioned in flexion or extension. There was no difference between the 2 groups in their initial responses to the SF36 quality of life questionnaire, nor in their level of anxiety or depression (HADS questionnaire). The mid-sagittal AP spinal canal diameter in both the surgical and non-surgical patients was distinctly smaller than that reported in the literature for normal men and women using similar imaging techniques. In both the surgical and no0n-surgical groups, 23% of patients had a mid-sagittal spinal canal diameter 10mm or less at the C5/6 disc space as measured on CT or MRI images. With the neck positioned in extension, 46% of surgical and non-surgical patients were found to have mid-sagittal AP spinal canal diameter 10mm or less at the C5/6 disc space as measured on CT images. Forty percent of patients in the surgical group had 3mm or more of tonsillar ectopia (mean 5.6mm) while 27% of the patients in the non-surgical group had a similar finding (mean 4.0mm) as measured in the traditional manner on the mid sagittal T1 weighted MRI image. No single structural cause for myelopathy was identified and therefore no single procedure was performed. The surgical treatment of myelopathy included suboccipital decompression, anterior cervical discectomy and fusion or cervical laminectomy with or without instrumented fusion as indicated by the neuroradiological findings. While we diagnosed and treated myelopathy, we monitored all symptoms. At the six month follow-up, there was a statistically significant improvement in the surgical group as compared to the non-surgical group regarding patient reported dizziness, limb numbness, pain, impaired balance and grip weakness (p=0.04 – p=0.000, Chi squared analysis). Improvement was noted in a number of symptoms associated with fibromyalgia and not usually associated with cervical myelopathy such as irritable bowel syndrome (p=0.003) and impaired memory (p=0.0007), impaired concentration (p=0.03) and disorientation (p=0.002). Headache improved in 90% of the surgical group and 45% of the non-surgical group (p=0.06). Patients in the surgical group were more likely to report and improvement in fatigue, depression, insomnia, limb paresthesiae, clumsiness and cold intolerance than were patients in the non-surgical group but the differences were not statistically significant. There was an improvement in all 9 subscales of the SF36 in the surgical as compared with the non-surgical group, (p=0.037 – p<0.0001, Wilcoxon rank sum test and Fisher’s exact test). Surgical treatment of cervical myelopathy associated with spondylotic cervical stenosis and/or the Chiari 1 malformation may result in the improvement of a vast array of symptoms usually attributed to fibromyalgia, with an associated improvement in patient quality of life. Despite non=randomization, the surgical and non-surgical patients were virtually identical in all measured parameters at the time of initial evaluation. However, as the patients were not randomized, the observed difference in outcome cannot be definitively or exclusively attributed to surgery. Nevertheless, our outcomes implicate a potential association between cervical myelopathy and fibromyalgia in some patients.
IS CERVICAL MYELOPATHY OVERLOOKED IN PATIENTS WITH FIBROMYALGIA? Dan Heffez, MD, et al
Fibromyalgia is a syndrome characterized by diffuse chronic pain. The American college of Rheumatology has established diagnostic criteria, which have been helpful in distinguishing fibromyalgia from other chronic pain states but have not advanced the understanding of its etiology. The worldwide prevalence of fibromyalgia is estimated to be 2%. An estimated six million Americans are affected. In addition to the widespread pain, patients complain of a variety of symptoms, including overwhelming fatigue exacerbated by exertion, headache, dizziness, cognitive difficulties, instability of gait, limb numbness and paresthesiae. Some physicians have come to view the syndrome as a somatization disorder because of these numerous and apparently unrelated complaints and because fibromyalgia fails to fit the biomedical cause-effect model. Many of the symptoms reported by fibromyalgia patients are identical to those reported by patients diagnosed with either Chiari 1 malformation or with cervical myelopathy due to spinal stenosis, (spondylotic cervical myelopathy), two well-defined neurological disorders. Therefore, we evaluated a cohort of patients who carried the diagnosis of fibromyalgia for objective evidence of cervical myelopathy. Two hundred and seventy (270) consecutive patients who carried the diagnosis of fibromyalgia were evaluated between September 1998 and May 2001. The sole requirement for referral was that the patient carry the diagnosis of fibromyalgia. On initial evaluation, patients completed a questionnaire detailing their symptoms, current medications and past medical consultations. A diagram depicting the distribution of the patient’s body pain and an analogue pain severity scale were completed. In order to insure that every patient was assessed in the same manner, they were evaluated by a neurologist and/or a neurosurgeon who, independent of each other, performed a neurological examination and recorded the findings on a standardized form. All data including the results of the examinations were entered into a relational database. Every patient underwent magnetic resonance imaging of the brain with special attention to the foramen magnum in order to exclude a Chiari 1 malformation. For the purpose of determining the position of the cerebellar tonsils the lower lip of the foramen magnum was defined as extending from the lowest cortical bone of the clivus anteriorly (basion) to the lowest cortical bone at the position posteriorly on themed sagittal MRI image. The position of the most caudal point of the tonsil(s) relative to the inferior lip of the foramen magnum was measured from the midsagittal MRI slice. MRI scan of the cervical spine was performed in order to identify any intrinsic spinal cord lesion capable of causing myelopathy. Every patient also underwent computed tomographic (CT) imaging of the cervical spine following the intravenous infusion of 150 ml of non-ionic contrast (300 mg of iodine/ml). The CT scan was performed with the patient’s neck in the neutral and then in the extended position. The gantry angle was altered to obtain images perpendicular to the spine at each level. The mid-sagittal anterior-posterior (AP) dimension of the spinal canal was determined at the level of the of intervertebral disc space on both neutral CT and MRI images and on CT images with the neck extended. MRI and CT images were individually scanned into a Pentium III personal computer using a Umax power look III scanner. One of two independent observers, unrelated to the medical evaluation or treatment of the patients, made measurements of the position of the cerebellar tonsils and the mid-sagittal AP spinal canal diameters using SigmaScan Pro software, version 5.0. Eighty-six percent of the patients were women. Ninety-seven percent were Caucasian. The mean age was 44 years (SD=11 years). The mean duration of symptoms was 8 years (std dev 67.3 yrs). Fifty-nine percent of patients reported antecedent craniospinal trauma within 3-6 months of the onset of symptoms. On average, the patients had consulted 10 different medical specialists during the course of their illness. Patients were taking a mean of 4.8 medications, (including but not limited to opiate and non-opiate analgesics, benzodiazepines, antidepressants, sedative hypnotics and muscle relaxants), for the relief of symptoms related to fibromyalgia. Forty-one percent of patients had at least a college education. Sixty-eight percent of patients had left their job as a direct result of their illness. The predominant complaints were neck/back pain (95%), fatigue (95%), exertional fatigue (96%), cognitive impairment (92%), instability of gait (85%), subjective grip weakness (83%), paresthesiae (80%), dizziness (71%) and numbness of the hands/feet (69%). Eighty-eight percent of patients reported worsening symptoms with neck extension. The findings of neurological examination were diagnostic of cervical myelopathy. An upper thoracic spinothalamic sensory level (T3-T6) was noted in 83% of patients: Typically, we detected hyperalgesia and allodynia to a cold or lightly applied pinprick stimulus below a dermatome level. Rarely, a suspended band of hypesthesia to cold or pinprick stimulus was detected between the third and seventh thoracic dermatomes. The second most common neurological finding, (noted in 64%of patients), was hyper-reflexia. Recruitment, (the pathological spread of reflexes beyond the muscle being tested), including inversion of the radial periosteal reflex was observed in 357% of patients. Other objective neurological findings included positive Romberg sign (29%), varying degrees of ankle clonus (25%), positive Hoffman signs (26%), impaired tandem walk (23%), dysmetria 915%) and disdiadochokinesia (13%). The patients were examined first with the neck in the neutral and subsequently in the flexed and then in the extended positions. Neck extension and neck flexion resulted in immediate accentuation of the abnormal pyramidal track findings in 88% and 73% of patients respectively, suggesting a mechanical etiology for the abnormal neurological findings. The MRI images of the brain did not show any consistent intrinsic disease of the brain, parenchyma. The only consistent finding was the caudal displacement of the cerebellar tonsils. The mean position of the cerebellar tonsils as measured on the mid sagittal MFI image was 1.1 mm (SD=4.4mm) below the rim of the foramen magnum. In 38% of patients the tonsillar herniation exceeded 3mm, (mean 5.6, SD=2.1 mm). In 20% of patients tonsillar ectopia exceeded 5 mm (mean=7.1, SD=1.8mm). MRI and contrast enhanced CT imaging of the cervical spine revealed a narrow canal. I.e. stenosis. The mean AP spinal canal diameter at C2/3, C3/4, C4/5, C5/6, C6/7 and C7T1 was 13.2, 11.7, 11.8, 10.7, 11.5 and 14.9 mm respectively, (CT images). In 23% of patients, the AP mid-sagittal spinal canal diameter was 10mm or less at the C5/6 intervertebral disc space measured 10mm or less in 46% of patients when the neck was positioned in extension, (CT images). MR imaging of the cervical spine did not reveal any consistent intrinsic spinal cord disease with the exception of signal hyper-intensity at the level of spondylotic spinal cord compression noted on the T2 sequence images in some patients. Symptoms of myelopathy are variable and can be quite vague, often leading to initial misdiagnosis. We have identified neurological findings diagnostic of cervical myelopathy in a selected cohort of 270 patients previously diagnosed with fibromyalgia. An upper thoracic sensory level has been described as a false localizing sign of cervical myelopathy. Recruitment of deep tendon reflexes is an upper motor neuron sign of pyramidal tract dysfunction. Inversion of the radial periosteal reflex is felt to be virtually diagnostic of myelopathy due to extrinsic compression of the spinal cord at the level of the fifth or sixth cervical vertebra. Neuroradiological findings were consistent with a treatable structural cause(s) for the myelopathy –i.e. spondylotic cervical stenosis and/or Chiari type 1 malformation. In 20% of our patients a radiological diagnosis of the Chiari 1 malformation could be made based on tonsillar ectopia in excess of 5mm. Meadows et al (J Neurosurgery 2000; 96:920-926), reviewed the brain and cervical spine MRI’s of 22,591 patients and could identify only 175 patients in whom tonsillar ectopia exceeded 5 mm, i.e. a prevalence of .77%. The CT scan of the cervical spine revealed cervical stenosis, which was accentuated by neck extension. Neck extension is known to reduce the AP spinal canal diameter. The stenosis in myelopathic patients has been described by Muhle et al, (Acta Radiologica 1999; 40:146-153), and Graham et al, (Clinical Radiology 2001; 50:35-39). The AP mid-saggital diameter at the C5/6 intervertebral disc space measured 10mm or less in 46% of patients with the neck placed in extension. A mid-sagittal diameter of 10mm is acknowledged as stenotic and consistent with symptomatic spinal cord compression, i.e. cervical myelopathy. Spondylotic cervical myelopathy and the Chiari 1 malformation are treatable conditions. Therefore, we recommend that a detailed neurologic examination should be incorporated into the evaluation of all patients with fibromyalgia. Evidence of cervical myelopathy would warrant neuroradiological examination of the brain and cervical spine and appropriate neurological referral.
Presenter: Michael J. Rosner, MDDr. Rosner received his undergraduate training at the University of Virginia and his MD, Neurosurgical training and first faculty appointment from the Medical College of Virginia where he was an Assistant Professor of Neurosurgery. He was and Associate Professor of Neurosurgery at the University of North Carolina School of Medicine at Chapel Hill. Dr. Rosner is the former Medical Director of the Neurosurgical Intensive Care Unit at University Hospital, University of Alabama at Birmingham and the Chairman of the American Association of Neurological Surgeons – sponsored Neurosurgery Critical Care Course. He is an eminent authority on Cerebral Perfusion Pressure, is widely published and a popular speaker. His research interest and publications center on Cerebral Perfusion Pressure as related to Traumatic Brain Injury. At the 1991 Eighth International Symposium on Intracranial Pressure in Rotterdam, Dr. Rosner received awards for presentations on “Cerebral Perfusion Pressure Management of Head Injury” and “Toxic Effects of Nutritional Support in the Severely Head Injured Patient”. Current research interests include Cerebral Perfusion Pressure (CPP) Management in the Control of Intracranial Pressure; Congenital Stenosis of Posterior Fossa and Cervical Spine with clinical syndrome, abnormalities of cerebral blood flow and metabolism, cognitive disorders, hydrocephalus and normal pressure hydrocephalus, and chronic fatigue and fibromyalgia syndromes.
The neurosurgical subset of fibromyalgia: Part I: Clinical findings with neurally mediated hypotension. Michael J. Rosner, Royce K. Bailey, Jorge Flechas Fibromyalgia is a syndrome characterized by low pain thresholds, but which may occasionally be a manifestation of surgically treatable disease. The hallmark of this subset of patients will be objective neurological abnormality. Objective: To define neurological abnormalities in patients who may be candidates for surgical decompression, to document symptomatic outcome at one-year after surgery (part II) and to document radiological differences between control and this subset of FMS patients (part III). Methods: 37 patients underwent protocol neurological and tilt table examinations that included a detailed neurological history/review of system and assessment of cranial nerve, motor, sensory, extrapyramidal and reflex evaluations. Each underwent a tilt table examination to objectively assess at least the cardiovascular component of the autonomic nervous system to restrict this subset to those with objectively defined organic disease. Results: Patients had been symptomatic for > 10 years and on disability for an average of 4.9 years. Cranial nerve deficits: 14/37 demonstrated unilateral or bilateral Horner’s syndrome. 21/37 had CN V abnormalities including absent corneal reflexes. 7/17 demonstrated CN VII abnormalities (not including dry eyes, dry mouth, or hyperacusis) and 17/37 had abnormalities of hearing (not including tinnitus). 20/37 had CN IX, X, XI abnormalities, most commonly absent gag reflex and oropharyngeal sensory changes. Abnormalities of convergence, nystagmus, head tilt, skew deviation, esophoria and tongue weakness were common. Upper extremity motor deficits were identified in 36/37 and 35/37 in the lower extremities. Hyper-, hypotonia and atrophy were frequent. 32/37 had abnormalities to pin, touch, vibration or temperature sensation. 24/37 demonstrated hyperreflexia, and 17/37 demonstrated hyporeflexia. 34/37 had abnormalities of gait, 27/37 a positive Romberg’s sign and Babinski’s and Hoffman’s sign were present in 18 and 8 of the 37 respectively. Conclusion: Neurological deficits can be identified in those patients with fibromyalgia syndrome and a positive tilt table examination. These deficits localize to the brainstem and upper cervical spinal cord and when identified should lead to a detailed radiological evaluation of these regions.
The neurosurgical subset of fibromyalgia: Part II: Radiological observations—patients vs. controls. Michael J. Rosner, Jorge Flechas, Royce K. Bailey Introduction: Clinical observations suggest the upper spinal cord and brainstem may be involved in a subset of patients with FM like symptoms. Objective: Test the hypothesis that there will be radiological differences related to the posterior fossa and/or cervical canal between control and the surgical subset of FMS patients. Methods: 37 patients carrying the diagnosis of ‘fibromyalgia’ were selected based upon an abnormal tilt table examination defining cardiovascular/autonomic dysfunction (NMH/POTS) and abnormalities identified from the neurological examination. Protocol magnetic resonance (MR) scans of the craniocervical junction region were accomplished for each patient in sagittal, coronal and transaxial planes; cerebrospinal fluid (CSF) flow via phase contrast MR was assessed. Specific grading of tonsillar descent (midline and paramedian), obex height, tonsillar impaction within the foramen magnum, vertebral artery invagination of the brainstem, and AP diameter of the foramen magnum was carried out. The spinal cord and canal diameters were measured at each disk level with electronic calipers. These results were compared with those of asymptomatic control patients. Systat 7.0 and Excel were used for data analysis; all values X + SD. Conclusion: FM-NMH/POTS patients with abnormal neurological examinations represent a population that is radiographically distinct from asymptomatic individuals. These differences relate to the brainstem and cervical spinal cord as suggested by neurological examinations. However, the overlap of standard deviations is such that simple review of MR scans will not discriminate between these groups independently of the neurological exam. INTRODUCTION: We have observed subtle radiographic changes on craniocervical MR scans of patients with neurological findings related to the brainstem and upper cervical spinal cord sufficient to explain clinical symptoms and physical findings. However, in most cases, these MR scans were reasonably read as “normal” by radiologists, leading the referring physician to seek other than structural etiologies for the patient’s complaints. This is an important error not to make, and we wish to establish a set of observations which might provide a core of information to help make an accurate radiological diagnosis in this group of patients. HYPOTHESES: The cerebellar tonsils will be lower in FMS patients when compared with controls. Similar hypotheses will be tested for differences between FMS patients and controls with regard to: Tonsillar impaction into the foramen magnum, vertebral artery impaction into the brainstem, and the AP diameter of the cervical canal at each level. Hypothesis statement and testing was of the form: H1: μ1 ≠ μ0 H0: μ1 = μ0
The neurosurgical subset of fibromyalgia: Part III: Functional and symptomatic outcome at 12 months post-operatively. Michael J. Rosner, Jorge Flechas, Royce K. Bailey Objective: Test the hypothesis that symptoms and function will be improved at 12 months after surgery when compared to the same measures obtained preoperatively. Methods: 37 patients were selected based upon an abnormal tilt table examination defining cardiovascular/autonomic dysfunction, abnormalities identified from the neurological examination, and supported by radiographic changes at the foramen magnum and or cervical canal. Patients then underwent decompression of the involved region. They were followed longitudinally with repeat neurological examinations, questionnaires for grading of symptoms including incremental and visual analog scales of outcome and/or symptomatic improvement. Systat 7.0 and Excel were used for data analysis (all values X + SD). Results: Ten measures of pain including joint pain, muscle pain, neck pain, headache, burning legs and others improved dramatically (p = 0.017-0.0000002). Dolorimetry is reported separately. Six cardiovascular symptoms including palpitations, SOB, dizziness, non-cardiac chest pain all improved (p= 0.016-0.000009). Excess fatigue decreased from a severe problem to a mild problem at 12 months (p=1.5E-9) along with three other measures of fatigue (p=0.00059-0.000007). Alimentary symptoms, cognitive complaints, sexual function, depression and others improved in a highly reliable fashion. The number of days/week patients felt “good” increased from 1.0 + 1.5 to 3.9 + 2.3 (p= 1.7E-11) at 12 months; only about 30% of patients were working pre-operatively compared with 80% at one year (p= 0.000015); this was paralleled by a large reduction in “days missed from work”. There were no surgical deaths, nor serious complications. No patient worsened neurologically. Conclusion: There is a subset of patients with radiological changes consistent with neurological abnormalities who can undergo posterior fossa and/or cervical decompression with important and long lasting improvement in quality of life as measured by their assessments of pain, multiple somatic symptoms, and the ability to function within the home and workplace. The risks of surgical decompression should be minimal. Fibromyalgia syndrome should not be used as a diagnosis for those with neurological findings.
Fibromyalgia: Part IV: Long term outcome as measured by dolorimetry. Flechas, J.D and Rosner, M.J. Objective: Previous studies of patients with spinal cord injury, such as laceration, compression, and/or injury have described a pain syndrome, which is descriptive of fibromyalgia syndrome (FMS) pain. We hypothesized that dolorimeter (DOL) scores would go up as a function of time after surgery to decompress the spinal cord in patients with FMS. Methods: All patients met the American College of Rheumatology classification criteria for FMS. Patients also had to demonstrate on MRI, spinal cord compression. Before surgery was considered, they had to show neurological dysfunction, such as numbness, limb weakness, neurally mediated hypotension etc. If their symptoms were well controlled by medication, surgery was not a consideration. At no time was surgery done for FMS pain. DOL was done at the time of initial office visit (IOV), prior to surgery (PTS), and at different times post op (PO) over the next year. Data was analyzed by student t test. Avg age 45. Conclusion: Spinal cord pain, which initially is mistaken as FMS pain, does statistically improve with decompression of the cord. The data supports that pain thresholds improve as a function of time.
Results: Units are as follows: DOL (kg/cm2)+SEM, Time (weeks)+SEM Time DOL N Std Dev P-Value IOV 43.7+2.7 62 21 PTS 43.2+3.2 63 21 6.4+.2 66.6+5.2 37 32 .00007 13+.4 79.1+7.5 31 42 .002
Neurally mediated hypotension (NMH) and positional orthostatic tachycardia syndrome (POTS): Part I: Associated neurological abnormalities. Michael J. Rosner, Royce K. Bailey, Jorge Flechas Introduction: NMH and POTS are cardiovascular dysautonomias. The diagnosis is confirmed by tilt table examination (phase I-without isoproterenol) or with tachycardia induced by isoproterenol (phase II). Neuroanatomically, these conditions relate to the brainstem and spinal cord, but have not usually been viewed as due to structural changes in the regions. Objective: To define associated neurological abnormalities in patients who may be candidates for surgical decompression, to document symptomatic outcome at one-year after surgery (part II) and to document radiological differences between control and this subset of FM patients (part III). Methods: 37 patients had undergone a positive tilt table examination. Each prospectively underwent an evaluation that included a detailed neurological history and examination, protocol craniocervical MR, and detailed questionnaire regarding symptoms. Results: Patients had been symptomatic for > 10 years and on disability for an average of 4.9 years. Cranial Nerve deficits: 14/37 demonstrated unilateral or bilateral Horner’s syndrome. 21/37 had CN V abnormalities including absent corneal reflexes. 7/17 demonstrated CN VII abnormalities (not including dry eyes, dry mouth, or hyperacusis) and 17/37 had abnormalities of hearing (not including tinnitus). 20/37 had CN IX, X, XI abnormalities, most commonly absent gag reflex and oropharyngeal sensory changes. Abnormalities of convergence, nystagmus, head tilt, skew deviation, esophoria and tongue weakness were common. Upper extremity motor deficits were identified in 36/37 and 35/37 in the lower extremities. Hyper-hypotonia and atrophy were frequent. 32/37 had abnormalities to pin, touch, vibration or temperature sensation. 24/37 demonstrated hyperreflexia, and 17/37 demonstrated hyporeflexia. 34/37 had abnormalities of gait, 27/37 a positive Romberg’s sign and Babinski’s and Hoffman’s sign were present in 18 and 8 of the 37 respectively. Conclusion: Neurological deficits can be identified in those patients with NMH/POTS. These deficits localize to the brainstem and upper cervical spinal cord and when identified should lead to a detailed radiological evaluation of these regions in search of remedial compression.
Neurally mediated hypotension (NMH) and positional orthostatic tachycardia syndrome (POTS): Part II: Radiological observations—patients vs. controls. Michael J. Rosner, Jorge Flechas, Royce K. Bailey Introduction: Clinical observations suggest the upper spinal cord and brainstem may be involved in a subset of patients with symptoms related to NMH/POTS. Objective: Test the hypothesis that there will be radiological differences related to the posterior fossa and/or cervical canal between control and those patients with NMH/POTS. Methods: 37 patients were selected based upon an abnormal tilt table examination defining cardiovascular/autonomic dysfunction and abnormalities identified from the neurological examination. Protocol magnetic resonance (MR) scans of the craniocervical junction region were accomplished for each patient in sagittal, coronal and transaxial planes; cerecerebrospinal fluid (CSF) flow via phase contrast MR was assessed. Specific grading of tonsillar descent (midline and paramedian), obex height, tonsillar impaction within the foramen magnum (FM), vertebral artery (VA) invagination of the brainstem, and AP diameter of the foramen magnum was carried out. The spinal cord and canal diameters were measured at each disk level with electronic calipers. These results were compared with those of asymptomatic control patients. Systat 7.0 and Excel were usef for data analysis; all values X + SD. Conclusion: NMH/POTS patients with abnormal neurological examinations represent a population that is radiographically distinct from asymptomatic individuals. These differences relate to the brainstem and cervical spinal cord as suggested by neurological examinations. However, the overlap of standard deviations is such that simple review of MR scans will not discriminate between these groups independently of the neurological exam. HYPOTHESES: The cerebellar tonsils will be lower in NMH/POTS patients when compared with controls. Similar hypotheses will be tested for differences between NMH/POTS patients and controls with regard to: tonsillar impaction into the foramen magnum, vertebral artery impaction into the brainstem, and the AP diameter of the cervical canal at each level. Hypothesis statement and testing was of the form: H1: μ1 ≠ μ0 H0: μ1 = μ0
Presenter: Andrei Krassioukov, MD, PhD Dr. Krassioukov graduated with Honours from the Volograd Medical School, Russia. Obtained his PhD at the Ivan Pavlov Institute of Physiology, Russian Academy of Science, St. Petersburg, Russia. In 1991, through the Canada-Russia medical-research exchange program, he joined the John P. Robarts Research Institute at the University of Western Ontario in London, ON. Presently, he is a clinical neurophysiologist and Research Director of Intraoperative Monitoring Group of the Division of Neurosurgery, Toronto Western Hospital. Dr. Krassioukov holds two academic appointments, viz., Assistant Professor, Department of Surgery at the University of Toronto, Toronto, ON, and Adjunct Professor, Department of Physical Medicine and Rehabilitation, at the University of Western Ontario in London, ON. Dr. Krassioukov has also been a visiting professor at the Johns Hopkins University, USA; University of Miami, USA; the Prefectural University of Kyoto, Japan; University of Florence, Italy and others. Dr. Krassioukov currently serves as a Scientific Advisor to the Geoffrey Lance Foundation. Research in his laboratory is focused on the mechanisms of autonomic dysfunction after spinal cord injury. In particular, he is interested in the mechanisms of autonomic dysreflexia, one of the most common and life threatening complications of spinal cord injury in humans. Lately, his research concentrated on investigation of plastic changes within spinal circuits after cord injury in humans. His experimental animal data and clinical research findings resulted in over sixty peer-reviewed manuscripts and book chapters. His research is supported by grants from the Medical Research Council of Canada, Heart and Stroke Foundation of Canada, Christopher Reeve Paralysis Foundation, American Association of Neurological Surgeons and Cervical Spine Research Society.
Autonomic dysfunction and pain in fibromyalgia: What can we learn from animal models? Andrei Krassioukov, MD, PhD Despite substantial clinical evidence and established criteria for the diagnosis of fibromyalgia (FM) we are still puzzled by the mechanisms underlying this debilitating condition. FM is a clinical syndrome characterized by chronic widespread pain and commonly associated with autonomic dysfunction. Numerous clinical investigations showed that patients with FM had a low threshold to pain, experienced a longer duration and a larger area of referral of experimentally induced pain. This suggests a state of disordered sensory processing in FM. Numerous clinical and experimental observations suggest that abnormal synthesis of the nerve growth factor (NGF) could be responsible for the development of hyperalgesia and autonomic dysfunction in different painful posttraumatic or inflammatory disorders. It was suggested that increased concentration of NGF in cerebrospinal fluid of patients with FM might be among the mechanisms involved in its development (Giovengo et al 1999). Spinal cord injury (SCI) associated with increased levels of NGF protein stimulates small-diameter primary afferent fibers sprouting. These afferent fibers contain calcitonin gene-related peptide and their arbors in the dorsal horn were significantly increased after SCI. This coincided with the development of autonomic dysfunction in these animals (Krenz et al 1999). Moreover, we have shown that concurrent with the development of autonomic dysfunction there was a widespread increase in responsiveness of spinal interneurons to the visceral or somatic pain stimulation in these animals (Krassioukov et al 2002). These fibers are unmyelinated afferent C-fibers and lightly myelinated afferent A delta fibers. Moreover, extent of small-diameter afferent sprouting after SCI correlated significantly with the magnitude of autonomic dysfunction. The aberrant sprouting and inappropriate synaptic connections within the spinal cord are probably responsible for the hyperresponsiveness of spinal circuits and widespread pain. Blocking intraspinal NGF with neutralizing antibody prevented not only sprouting of these fibers but also ameliorated autonomic dysfunction in animals with experimental SCI. Our experimental data from animals with SCI provide insight into the pathophysiology of widespread pain, allodynia, and autonomic dysfunction that could be partially involved in the development of these conditions in patients with FM.
1 Giovengo S.L., I.J. Russell and A.A. Larson. Increased concentration of NGF in cerebrospinal fluid of patients with FM. J. Rheumatology. 26: 1564-1569, 1999. 2 Krenz N.R., S.O. Meakin, A.V. Krassioukov and L.C. Weaver. Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury. J. Neuroscience. 19(17) 7405-14, 1999. 3 Krassioukov, A.V., D.G. Johns and L.P. Schramm. Sympathetically correlated activity and responses to different stimuli of dorsal horn neurons in acute and chronic spinal cord-injured rats. J. Neurotrauma. 2002 (In Press).
Presenter: Jennifer M. Glass, PhD Dr. Glass is a Cognitive Psychologist working at the Institute for Social Research and Addiction Research Center at the University of Michigan. She studies cognitive function in people with fibromyalgia and other chronic, multi-symptom illness. Another research project focuses on the cognitive changes that occur as part of normal aging. A third project studies the cognitive risk factors for developing alcoholism.
Cognitive Dysfunction in Fibromyalgia Jennifer M. Glass Fibromyalgia patients frequently report that cognitive function, memory, and mental alertness have declined. A small but growing body of literature suggests that there is indeed cognitive dysfunction in fibromyalgia. In this talk, I address several questions that people my have about this dysfunction, including the types of cognitive tasks that have are problematic for fibromyalgia patients and the role of psychological and physical factors. Critical areas for further investigation will be highlighted, as well as preliminary findings form new studies.
PRESENTER: MARTIN SCHARF, PHD Martin B. Scharf was born in Cleveland, Ohio on October 14, 1946. He attended Ohio State University and received his BA from UCLA in 1968. He completed his doctoral training at Penn State University and received his Ph.D. in Pharmacology in 1979. Dr. Scharf was the Associate Director of the first Sleep Disorders Clinic in the country and has remained a leader in the field of Sleep Disorders Medicine ever since. He has authored or co-authored over 200 papers and notes pertaining to sleep disorders and the pharmacology of sleep and is considered to be one of the nation’s foremost authorities on the effects and effectiveness of drugs on sleep. He has been involved in the research and development of nearly every sleeping pill currently available in the U.S. His Center has also become one of the national leaders for the treatment of narcolepsy, becoming the first U.S. center to treat patients with the experimental compound, Gammahydroxybutyrate. He currently is the founder and director of the Center for Research in Sleep Disorders located in Cincinnati, Ohio. He is a Clinical Professor of Psychiatry at the Wright State University School of Medicine in Dayton, Ohio. He has appeared on many television and radio talk shows, including “Today”, “Oprah”, “20/20”, “Sally Jessy Rafael”, “Hour Magazine”, “Good Morning America”, and many others.
THE EFFECTS SODIUM OXYBATE ON CLINICAL SYMPTOMS AND SLEEP PATTERNS IN FIBROMYALGIA Martin B. Scharf, PhD, Margaret Baumann, David V. Berkowitz, MD The Tri-State Sleep Disorders Center, Cincinnati, OH
Background: Fibromyalgia is associated with the sleep phenomenon of alpha intrusion, and with low growth hormone secretion. Sodium oxybate has been shown to increase both slow-wave sleep and growth hormone levels. This double-blind, randomized, placebo-controlled, crossover trial was conducted to evaluate the effects of sodium oxybate on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic (PSC) sleep parameters of alpha instrusion, slow-wave (Stage 3/4 sleep), and sleep efficiency in fibromyalgia patients. Methods: Patients received either 6.0 g/d sodium oxybate or placebo for 1 month, with an intervening 2-week washout period. Efficacy measures included PSG evaluations, tender point index (TPI), and subjective measurements from daily diary entries. Safety measures included clinical laboratory values, vital signs, and adverse events. Results: Twenty-four female patients were included in the study; 18 completed the trial. TPI was decreased from baseline by 8.5, compared with an increase of 0.4 for placebo (p=0.0079). Six of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end of day fatigue, overall fatigue, and morning fatigue) were relieved by 29% to 33% with sodium oxybate, compared with 6% to 10% relief with placebo (p<0.005). Alpha intrusion, sleep latency, and REM sleep were significantly decreased, while slow-wave (Stage 3/4) sleep was increased significantly, compared with placebo (p<0.005). Two of the 5 subjective sleep-related variables were significantly different from placebo – morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; p=0.0033) and quality of sleep (improved by 33% and 10% respectively; p=0.0003). Conclusions: In this study, sodium oxybate effectively reduced the symptoms of pain and fatigue in fibromyalgia, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with the non-restorative sleep characteristic of this disorder. Key words: fibromyalgia, sodium oxybate, sleep patterns, alpha intrusion, sleep quality, non-restorative sleep, slow-wave sleep.
PRESENTER: KIM DUPREE JONES, RN, PHD, FNP Kim Dupree Jones is the Assistant Professor at the Oregon Health and Science University School of Nursing. She received her BSN degree from the University of Tennessee, her MN in Nursing/FNP at Emory University and her PhD and Post-Doctorate at Oregon Health and Science University. Currently she is the Assistant Professor or Graduate Teaching Assistant, Primary Health Care Nurse Practitioner Programs at Oregon Health & Science University School of Nursing. Prior to her tenure at OHSU, she was an Assistant Professor at Georgia State University in the Family Nurse Practitioner Program. Dr. Jones’ most current published papers include work with Dr. Robert Bennett’s fibromyalgia group at OHSU. Recently, they were awarded an NIH grant to study pyridostigmine bromide and exercise in FM patients. The GH stimulating effect of this drug is impressive and far more cost effective than growth hormone.
Maximizing the Efficacy of Exercise in Fibromyalgia by Manipulating the Growth Hormone Axis Kim Dupree Jones PhD By definition, people with fibromyalgia (FM) have chronic widespread pain and specified tender point areas. Other symptoms associated with FM include disrupted sleep, fatigue, decreased cognition, visceral and other pain syndromes, neurological symptoms, post-exertional muscle pain and exercise intolerance. The majority of people with FM are known to be aerobically unfit, have poor muscle strength and limited flexibility. Deconditioned muscle is theoretically more prone to muscle microtrauma, which causes localized pain and triggers widespread pain through disordered central nervous system processing (i.e., central sensitization). A negative cycle of decondititioning occurs in FM in large part due to exercise-induced pain that limits exercise tolerance. Dysfunction of the hypothalamic-somatotropic axis, specifically growth hormone (GH)/insulin-like growth factor-one (IGF-1), may also contribute to exercise induced pain and exercise intolerance in FM, due to the critical role of GH/IGF-1 in muscle homeostasis and repair following exercise. Our research team has demonstrated that approximately one-third of 500 women with FM tested have low IGF-1 levels. Furthermore, in a 9 month placebo controlled, blinded study, we demonstrated that daily subcutaneous injection of recombinant GH in women with FM increases resting IGF-1 levels (70-110%) and improves FM symptoms, especially pain and exercise tolerance. The majority of participants in that study achieved statistically significant symptomatic improvement at 6 months, a key piece of the rationale for the length of our proposed intervention. Most recently we found that women with FM, regardless of IGF-1 levels, failed to produce an expected surge of GH in response to acute exercise. However, the women did produce a normal GH surge if given a single low dose tablet of oral pyridostigmine bromide before acute exercise. Pyridostigmine bromide is a cholinergic agent which, in animals, has been found to stimulate the release of GH by decreasing hypothalamic somatostatin tone. Elevated hypothalamic somatostatin tone is hypothesized to be responsible for GH dysfunction in FM. We know from our previous work that women with FM who can tolerate exercise training show significant improvement in symptoms, overall fitness, and related health parameters with training. We are currently undertaking an NIH funded 4 arm randomized placebo controlled trial of exercise and pyridostigmine bromide. We hypothesize that through normalization of GH profiles, women with FM will better tolerate an exercise training regimen and thereby demonstrate improved fitness and fewer FM symptoms by the end of the training period. We will capitalize on the GH stimulating effect of pyridostigmine bromide rather than recombinant GH for cost effectiveness ($40/month compared with $1,100/month), ease of administration (oral rather than injectable), more favorable side-effect profile, and promising pilot data in FM.
PRESENTER: Andrew J. Holman, MD Andrew J. Holman MD, is Assistant Clinical Professor of Medicine at the University of Washington and practices rheumatology at Valley Medical Center in a Seattle suburb. He completed his undergraduate studies at Bowdoin College in 1981 and received his medical degree from the University of Missouri-Columbia in 1987. His internal medicine residency training was completed at Denver Presbyterian Medical Center in 1990. After his rheumatology fellowship at the University of Washington, he has practiced clinical rheumatology while exploring new options for fibromyalgia and autoimmune connective tissue diseases. His research focuses on autonomic dysregulation, hypermobility syndrome and how the autonomic nervous system interacts with the immune system. His hypothesis that autonomic arousal from deep, restorative sleep underlies the pathogenesis of fibromyalgia led to American College of Rheumatology poster presentations in 1998-2000 describing the use of Restless Legs Syndrome options for fibromyalgia. Ultimately, this work led to use of dopamine agonists for fibromyalgia, a technique approved by US patent in 2001. Further examination of second-generation, dopamine-3 receptor specific agonists, including pramipexole and ropinirole, are ongoing. From work by Harvey Moldofsky, MD, and others, fibromyalgia is associated with altered sleep stages, and particularly, depleted deep, non-REM, stage III-IV. Efforts to restore these stages with medications known to increase stage IV sleep have provided only sporadic and partial relief of fibromyalgia (FM) symptoms. Often these options, including muscle relaxants and nighttime and antidepressants, led to side effects and intolerances. Consequently, many new approaches have been considered for patients with fibromyalgia from many different points of view. To reconsider that fibromyalgia may actually be the predictable consequence of deep sleep deprivation, the mechanism of arousal from deep sleep may be a more important therapeutic target. Many problems fragment and distort normal sleep stage architecture, including stress, pain, fear, and other stimulatory concerns. While many patients deal with a variety of concerns affecting sleep, the arousal mechanism may be the common denominator that expresses these varied stimuli. The fight-or-flight response is an autonomic function and it should readily inhibit deep sleep. Expressions of autonomic arousal or increased sympathetic tone may include disruptive dreams, racing thoughts and the stress response, but possible also bruxism, restless legs syndrome (RLS) and periodic limb movement. Therefore, medications addressing RLS may decrease that arousal mechanism that inhibits deep sleep.
ABSTRACT: ANDREW HOLMAN, MD Preliminary open label evaluations of lorzepam and clonazepam suggested that combining these mild RLS agents with a medication known to increase deep sleep decreases fibromyalgia pain scores. All Parkinson’s medications treat RLS, and adding Levo-Dopa (Sinemet) can decrease FM pain for some. The non-specific dopamine agonists also have a modest beneficial effect for FM, but the second-generation dopamine agonists reveal more promise. Pramipexole and ropinirole are dopamine-3 specific receptor agonists, FDA approved for Parkinson’s disease, but most commonly used for RLS at night. Early open label evaluation demonstrates their potential use in FM. An open label, multi-center evaluation will be presented at the American College of Rheumatology meeting in New Orleans in October 2002, and additional randomized, blinded studies are planned.
PESENTER: Jay D. Kranzler, MD, PhD Dr. Kranzler earned his M.D. at Yale University with a concentration in Psychiatry and earned his Ph.D. in Pharmacology for his thesis work on biochemical gender differences in the brain. He graduated summa cum laude from Yshiva University where he was a Belkin Scholar. In 1995 he was appointed Chief Executive Officer of Cypress Bioscience, Inc. During his tenure, Cypress successfully raised $50 million in new funding, received FDA approval to market the Company’s former product, the PROSORBAâ column for rheumatoid arthritis, and executed multiple license agreements. Previously, Dr. Kranzler served as President, Chief Executive Officer and a Director of Cytel’s technology base, raised $73 million through public offerings and acquired two technology companies, glycogen and Receptor Laboratories, to augment the company’s technology base. Under his leadership, Bytel secured five strategic alliances with major pharmaceutical companies – Upjohn, Sandoz, Sumitomo, Takara and Schwartz Pharma – which raised more than $150 million in research and development funding and equity investments. Dr. Kranzler founded Sequel Therapeutics in 1992 and served as President, Chief Executive Officer and Chairman of the Board for this joint venture with The Scripps Research Institute, which is now wholly owned by Cytel. He also co-founded Blytec Corporation in 1989 and served as President, Chief Executive Officer and Director until its acquisition by Cytel in 1990. Dr. Kranzler is an Adjunct Member of the Scripps Research Institute and has contributed to articles that have appeared in leading industry and scientific journals. From 1985 to January 1989, Dr. Kranzler was a management consultant with the international consulting firm McKinsey & Company, where he worked with many of the world’s leading pharmaceutical and technology companies conducting technology assessments, optimizing operating performance, evaluating research and development opportunities and structuring mergers and acquisitions.
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