Objective To describe the natural history of afferent baroreflex failure (ABF) based on systemati... more Objective To describe the natural history of afferent baroreflex failure (ABF) based on systematic review of clinical and laboratory data in patients with a diagnosis of ABF at Mayo Clinic Rochester. Methods We performed a retrospective chart review of all patients who underwent standardized autonomic reflex testing between 2000 and 2020 and had confirmation of the diagnosis of ABF by an autonomic disorders specialist. Patients were identified using a data repository of medical records. Variables included demographic, all-cause mortality, medications, ABF manifestations, comorbidities, and laboratory (autonomic testing, blood pressure monitoring, echocardiogram, brain imaging, plasma catecholamines, serum sodium level, and kidney function tests). Results A total of 104 patients with ABF were identified. Head and neck radiation was the most common etiology (86.5%), followed by neck surgery (5.8%) and other causes (7.7%). The most common findings were hypertension (87.5%), fluctuating blood pressure (78.8%), orthostatic hypotension (91.3%), syncope (58.6%), headache (22.1%), and tachycardia (20.2%). Patients commonly received antihypertensives (66.3%), pressor agents (41.3%), or a combination of both (19.2%). The median latency from completion of radiation to ABF was longer compared to the latency in the surgery group (p < 0.0001). Comorbidities, including complications from neck radiation, were frequently seen and all-cause mortality was 39.4% over a 20-year period. Conclusions ABF should be suspected in patients with prior head and neck cancer treated by radiation or surgery who present with labile hypertension and orthostatic hypotension. Management may require both antihypertensive and pressor medications. The morbidity and mortality in ABF are high.
Journal of The Peripheral Nervous System, Feb 1, 2003
ABSTRACT Guillain-Barre syndrome (GBS) is a monophasic illness. Early nadir and lack of multiple ... more ABSTRACT Guillain-Barre syndrome (GBS) is a monophasic illness. Early nadir and lack of multiple relapses have differentiated it from the chronic form (CIDP). We present a case whose unusual course overlaps both disorders. A 71-year-old man presented with paresthesiae and weakness evolving over 1-week period, 2 weeks after an upper respiratory infection. Spinal fluid analysis and electrophysiologic findings supported the clinical diagnosis of GBS. He was treated with a 5-day course of IVIG with rapid, almost complete recovery over the following 10 days. Four weeks later, his symptoms recurred. Another dose of IVIG produced rapid but transient improvement. He was started on oral steroids but continued to deteriorate. Clinical and laboratory reevaluation confirmed the presence of an inflammatory polyradiculopathy; IVIG was resumed. Over the following 3 months, his clinical course was characterized by 3 increasingly severe deteriorations, the last one to quadriplegia, severe bulbar dysfunction requiring tracheostomy and PEG placement, ophthalmoplegia and autonomic dysfunction. Transient improvements occurred between these relapses. Aggressive treatment, which included IVIG, plasma exchange, IV steroids and IV cyclophosphamide, did not produce sustained benefit. He remained pseudo-locked-in for 10 days. Another 5-day IVIG course was completed; he began to improve and continued to do so over the following 5 weeks. The nadir of GBS is usually reached within 4 weeks. Treatment fluctuations usually occur within the first weeks, and relapse during the recovery phase is often limited and isolated. Multiple relapses until a defined nadir are highly uncommon. The bulbar and cranial nerve involvement, rapidity of the relapses, dysautonomia, need for mechanical ventilation, and improving electrophysiology all argue against the diagnosis of CIDP. It remains unknown whether repeated doses of IVIG could change the natural course of this disease leading to such an unusual temporal profile.
Purpose of review The review focuses on the practical evaluation and management of patients with ... more Purpose of review The review focuses on the practical evaluation and management of patients with autonomic neuropathies. Recent findings Autonomic neuropathies are complex disorders and result in diverse clinical manifestations that affect the cardiovascular, gastrointestinal, urogenital, and sudomotor systems. The autonomic medical history is key when seeing a patient with suspected autonomic neuropathy. The history guides the clinical evaluation, laboratory testing, and autonomic testing in patients with autonomic neuropathies. The treatment of autonomic neuropathies is based on the combination of disease-modifying therapies, symptomatic pharmacologic therapies, and nonpharmacological management. Response to treatment can be assessed with quantitative autonomic biomarkers. Summary Treatment of autonomic neuropathies should be individualized, guided by disease state, medications’ mechanism of action and adverse event profile as well as cost. Genetic discoveries and pathologic understanding lead to the development of disease-modifying therapies as seen in familial amyloid polyneuropathy.
Clinical and Experimental Dermatology, Feb 27, 2012
Erythromelalgia is a rare disorder characterized by the clinical syndrome of burning pain, warmth... more Erythromelalgia is a rare disorder characterized by the clinical syndrome of burning pain, warmth and redness of the limbs. Neurological abnormalities (both large- and small-fibre neuropathy) are common. There have been few published reports on the sensory status of patients with erythromelalgia. To investigate the results of quantitative sensation testing in erythromelalgia using computer-assisted sensory evaluation, including vibratory detection threshold, cool detection threshold and heat-pain threshold (HPT). Patients who underwent dermatological or neurological evaluation of suspected erythromelalgia at our institution and received a final diagnosis of erythromelalgia were identified from a master diagnosis index covering the period January 1994 to June 2008. A retrospective chart review was performed. Main outcome measures were sensory abnormalities (e.g. pain, burning sensation, tingling) in response to heat, cooling and vibration during computer-assisted sensory testing. In total, 41 patients with erythromelalgia were enrolled in the study and underwent computer-assisted sensory evaluation. Of these, 34 patients (82.9%) had abnormal results. The commonest abnormality was isolated HPT: 11 patients (26.8%) had heat hypoalgesia and 18 (43.9%) had heat hyperalgesia, whereas only 2 (4.9%) of the healthy control patients had hyperalgesia on testing. Multiple sensory modalities were found to be abnormal in patients with erythromelalgia, with the commonest clinical abnormality being isolated heat-pain abnormality. These findings lend support to the notion that neuropathy underlies the clinical diagnosis of erythromelalgia. Future studies will explore the nature of the relationship between these sensory abnormalities and the clinical features of erythromelalgia.
OBJECTIVE: To report a positive outcome using a spinal cord stimulator in the treatment of pain s... more OBJECTIVE: To report a positive outcome using a spinal cord stimulator in the treatment of pain secondary to trigeminal trophic syndrome, previously refractory to medical management. BACKGROUND: Trigeminal trophic syndrome (TTS) is an unusual consequence of injury to the trigeminal nerve, characterized by the clinical triad of unilateral trigeminal anesthesia, facial dysesthesias and non-healing skin ulcerations, especially of the lateral nasal ala. Whether ulcerations occur secondary to self-manipulation alone remains a matter of debate. Some theorize that TTS is caused by dysregulation of neurotrophic factors, with self-manipulation playing an exacerbating role. Pain associated with TTS can be extremely challenging to treat and quite debilitating. Various neurological and dermatological case reports have detailed methods of pain treatment, including oral and topical agents. Successful treatment of TTS pain with a spinal cord stimulator, however, has not been reported. DESIGN/METHODS Case Report. RESULTS: We present a 25 year old female patient who developed TTS following four microvascular decompression procedures of the trigeminal nerve for the treatment of trigeminal neuralgia. In the year following her final decompression which also included a partial sectioning of the trigeminal nerve, facial ulcers began to appear, first inside her nostril, then elsewhere in the maxillary and mandibular regions and later on her forehead. She experienced significant pruritus and dysesthesias around these ulcers, and continued to have trigeminal neuralgiform pain. She tried multiple medications with the goal of controlling her pain, with none providing sufficient relief. These included multiple antiepileptics, tricyclic antidepressants, topical medicines, and opiates. She ultimately had a cervicomedullary junction spinal cord stimulator placed which resulted in 70-80% pain reduction, enabling her to taper off all opiates. CONCLUSIONS: Cervicomedullary junction spinal cord stimulation may be a treatment option in cases of refractory pain due to trigeminal trophic syndrome. Study supported by: N/A Disclosure: Dr. Golden has nothing to disclose. Dr. Robertson has nothing to disclose. Dr. Moossy has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Garza has received personal compensation for activities with UpToDate as an author. Dr. Garza has received personal compensation in an editorial capacity for Current Neurology and Neuroscience Reports.
OBJECTIVE: To compare the sensitivity of autonomic testing with that of current consensus criteri... more OBJECTIVE: To compare the sensitivity of autonomic testing with that of current consensus criteria in a large cohort of patients with autopsy-confirmed Multiple System Atrophy (MSA). BACKGROUND: Diagnostic Consensus Criteria for MSA are widely accepted as gold standard for the diagnosis of MSA. Neurologists at Mayo rely heavily on autonomic testing in their diagnostic considerations of patients with MSA, supported by our previous work establishing high sensitivity/specificity of autonomic testing in the differentiation of MSA from other synucleinopathies. A direct comparison of the value of consensus criteria versus autonomic testing in the diagnosis of MSA is lacking. DESIGN/METHODS: 49 autopsy-confirmed cases of MSA were included. Clinical data at the time of first presentation to Mayo were reviewed and consensus criteria applied. Standardized autonomic testing was reviewed and scored using a validated composite autonomic severity score (CASS, 0-10). Results of thermoregulatory sweat testing were documented as [percnt] anhidrosis (TST, 0-100[percnt]). CASS score 蠅5 and TST-anhidrosis 蠅30[percnt] were used as criteria for autonomic failure consistent with MSA. RESULTS: Of 49 MSA cases, 28 (57[percnt]) were male. Age at presentation was 60.5±7.8 years. 67[percnt] were MSA-p. Symptoms had been present for 4.5±3.1 years, time to death from presentation was 3.4±2.1 years. Only 57[percnt] fulfilled consensus criteria for probable and 82[percnt] for possible MSA. The reasons for not meeting criteria were 1) clinically significant levodopa-response, 2) circumstances preventing an adequate levodopa trial, and 3) autonomic or motor criteria not fulfilled. In contrast, 45 patients (92[percnt]) had a CASS蠅5, and 81[percnt] had TST-anhidrosis 蠅30[percnt]. CONCLUSIONS: Our data suggest that autonomic testing can markedly increase the sensitivity of current consensus criteria and allow for increased diagnostic certainty. Future revisions to the consensus criteria may benefit from softening the requirement of levodopa responsiveness, and adding autonomic laboratory criteria. Supported by NIH (P01NS44233, U54NS065736, K23NS075141, UL1RR24150), Mayo Funds. Disclosure: Dr. Singer has received license fee payments from Jacobus Pharmaceutical. Dr. Schmeichel has nothing to disclose. Dr. Parisi has nothing to disclose. Dr. Benarroch has received personal compensation in an editorial capacity for Neurology. Dr. Fealey has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Ahlskog has nothing to disclose. Dr. Bower has nothing to disclose. Dr. Matsumoto has nothing to disclose. Dr. Low has received personal compensation for activities with Chelsea Therapeutics, Pfizer Inc., and WR Medical Electronics Company as a consultant.
Autonomic Neuroscience: Basic and Clinical, Nov 1, 2015
Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative... more Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter natural history study of the NIH-sponsored U.S. Autonomic Disorders Consortium. Methods: Patients with a clinical diagnosis of MSA were prospectively enrolled at 5 participating centers. Demographic data, clinical variables, and autonomic testing results were included. Results: One hundred and nine patients with MSA (45 women) have been enrolled. MSA-C was predominant (60 patients, 55%). Mean age at symptom onset was 56.5 ± 8.8 and at enrollment was 61.2 ± 8.04 years old. MiniMental score was 28.9 ± 1.4 indicating normal cognition. Both the E:I ratio (1.09 ± 0.08) and the Valsalva ratio (1.24 ± 0.28) were low, indicating cardiovagal impairment. In the supine position, blood pressure (SBP/DBP)was 146 ± 24/82 ± 15mmHg, and heart rate (HR) was 74 ± 11 bpm (mean± SD). After 3-min head-up tilt, BP fell to 111 ± 23/67 ± 16mmHg andHR increased to 82 ± 11 bpm. Plasma norepinephrine level while supine was 278 ± 163 pg/ml and increased only to 409 ± 229 pg/ml upon head-up tilt indicating impaired baroreflex-mediated sympathetic activation. UPSIT score was 32.3 ± 4.1 indicating preserved olfaction. Symptoms suggesting REM behavior disorder were reported by 67%. Conclusions: Our results confirm that: i) symptom onset in MSA is remarkable consistent at 56 years; ii) overt cognitive impairment is not a typical feature; iii) sympathetic and cardiovagal deficits are present; iv) olfaction is preserved, and; v) sleep behavioral problems are frequent. Longitudinal evaluation of these patients will provide additional information on the natural history of the disease.
OBJECTIVE To assess the long-term neurological safety of tanezumab, a monoclonal antibody against... more OBJECTIVE To assess the long-term neurological safety of tanezumab, a monoclonal antibody against nerve growth factor. METHODS Patients with osteoarthritis of the hip or knee received stable doses of oral nonsteroidal anti-inflammatory drugs (NSAIDs) before study entry and during a ≤ 37-day screening period. Patients were randomized 1:1:1 to double-dummy tanezumab (2.5 mg or 5 mg, subcutaneous every 8 weeks) or oral NSAIDs (twice-daily) for 56 weeks, with a 24-week follow-up. Neurological safety evaluation focused on peripheral and sympathetic adverse events (AEs), neurologic examinations, and consultations with blinded, external diagnostic reviews. RESULTS During the treatment period, 6.2%, 9.0%, and 4.6% of patients experienced AEs of abnormal peripheral sensation (APS) in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. Hypoesthesia, paresthesia, and carpal tunnel syndrome were the most common AEs of APS. Clinically significant worsening on examination occurred in <1% in any treatment group at the last study assessment. Diagnoses following external neurological consultation included mononeuropathy (1.3%, 2.1%, and 1.0%), radiculopathy (0.9%, 0.4%, and 0.5%), and polyneuropathy (0.3%, 0.5%, and 0%) in tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. AEs potentially associated with sympathetic neuropathy were reported for 1.8%, 2.3%, and 2.9% of patients in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. No patient was diagnosed with sympathetic neuropathy. CONCLUSION Tanezumab had an increased incidence of AEs of APS versus NSAID; these were typically mild/moderate in severity, resolved during the study, and rarely resulted in discontinuation. Tanezumab was not associated with peripheral neuropathy and did not adversely affect the sympathetic nervous system. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT02528188 (https://clinicaltrials.gov/ct2/show/NCT02528188).
Objective To describe the natural history of afferent baroreflex failure (ABF) based on systemati... more Objective To describe the natural history of afferent baroreflex failure (ABF) based on systematic review of clinical and laboratory data in patients with a diagnosis of ABF at Mayo Clinic Rochester. Methods We performed a retrospective chart review of all patients who underwent standardized autonomic reflex testing between 2000 and 2020 and had confirmation of the diagnosis of ABF by an autonomic disorders specialist. Patients were identified using a data repository of medical records. Variables included demographic, all-cause mortality, medications, ABF manifestations, comorbidities, and laboratory (autonomic testing, blood pressure monitoring, echocardiogram, brain imaging, plasma catecholamines, serum sodium level, and kidney function tests). Results A total of 104 patients with ABF were identified. Head and neck radiation was the most common etiology (86.5%), followed by neck surgery (5.8%) and other causes (7.7%). The most common findings were hypertension (87.5%), fluctuating blood pressure (78.8%), orthostatic hypotension (91.3%), syncope (58.6%), headache (22.1%), and tachycardia (20.2%). Patients commonly received antihypertensives (66.3%), pressor agents (41.3%), or a combination of both (19.2%). The median latency from completion of radiation to ABF was longer compared to the latency in the surgery group (p < 0.0001). Comorbidities, including complications from neck radiation, were frequently seen and all-cause mortality was 39.4% over a 20-year period. Conclusions ABF should be suspected in patients with prior head and neck cancer treated by radiation or surgery who present with labile hypertension and orthostatic hypotension. Management may require both antihypertensive and pressor medications. The morbidity and mortality in ABF are high.
Journal of The Peripheral Nervous System, Feb 1, 2003
ABSTRACT Guillain-Barre syndrome (GBS) is a monophasic illness. Early nadir and lack of multiple ... more ABSTRACT Guillain-Barre syndrome (GBS) is a monophasic illness. Early nadir and lack of multiple relapses have differentiated it from the chronic form (CIDP). We present a case whose unusual course overlaps both disorders. A 71-year-old man presented with paresthesiae and weakness evolving over 1-week period, 2 weeks after an upper respiratory infection. Spinal fluid analysis and electrophysiologic findings supported the clinical diagnosis of GBS. He was treated with a 5-day course of IVIG with rapid, almost complete recovery over the following 10 days. Four weeks later, his symptoms recurred. Another dose of IVIG produced rapid but transient improvement. He was started on oral steroids but continued to deteriorate. Clinical and laboratory reevaluation confirmed the presence of an inflammatory polyradiculopathy; IVIG was resumed. Over the following 3 months, his clinical course was characterized by 3 increasingly severe deteriorations, the last one to quadriplegia, severe bulbar dysfunction requiring tracheostomy and PEG placement, ophthalmoplegia and autonomic dysfunction. Transient improvements occurred between these relapses. Aggressive treatment, which included IVIG, plasma exchange, IV steroids and IV cyclophosphamide, did not produce sustained benefit. He remained pseudo-locked-in for 10 days. Another 5-day IVIG course was completed; he began to improve and continued to do so over the following 5 weeks. The nadir of GBS is usually reached within 4 weeks. Treatment fluctuations usually occur within the first weeks, and relapse during the recovery phase is often limited and isolated. Multiple relapses until a defined nadir are highly uncommon. The bulbar and cranial nerve involvement, rapidity of the relapses, dysautonomia, need for mechanical ventilation, and improving electrophysiology all argue against the diagnosis of CIDP. It remains unknown whether repeated doses of IVIG could change the natural course of this disease leading to such an unusual temporal profile.
Purpose of review The review focuses on the practical evaluation and management of patients with ... more Purpose of review The review focuses on the practical evaluation and management of patients with autonomic neuropathies. Recent findings Autonomic neuropathies are complex disorders and result in diverse clinical manifestations that affect the cardiovascular, gastrointestinal, urogenital, and sudomotor systems. The autonomic medical history is key when seeing a patient with suspected autonomic neuropathy. The history guides the clinical evaluation, laboratory testing, and autonomic testing in patients with autonomic neuropathies. The treatment of autonomic neuropathies is based on the combination of disease-modifying therapies, symptomatic pharmacologic therapies, and nonpharmacological management. Response to treatment can be assessed with quantitative autonomic biomarkers. Summary Treatment of autonomic neuropathies should be individualized, guided by disease state, medications’ mechanism of action and adverse event profile as well as cost. Genetic discoveries and pathologic understanding lead to the development of disease-modifying therapies as seen in familial amyloid polyneuropathy.
Clinical and Experimental Dermatology, Feb 27, 2012
Erythromelalgia is a rare disorder characterized by the clinical syndrome of burning pain, warmth... more Erythromelalgia is a rare disorder characterized by the clinical syndrome of burning pain, warmth and redness of the limbs. Neurological abnormalities (both large- and small-fibre neuropathy) are common. There have been few published reports on the sensory status of patients with erythromelalgia. To investigate the results of quantitative sensation testing in erythromelalgia using computer-assisted sensory evaluation, including vibratory detection threshold, cool detection threshold and heat-pain threshold (HPT). Patients who underwent dermatological or neurological evaluation of suspected erythromelalgia at our institution and received a final diagnosis of erythromelalgia were identified from a master diagnosis index covering the period January 1994 to June 2008. A retrospective chart review was performed. Main outcome measures were sensory abnormalities (e.g. pain, burning sensation, tingling) in response to heat, cooling and vibration during computer-assisted sensory testing. In total, 41 patients with erythromelalgia were enrolled in the study and underwent computer-assisted sensory evaluation. Of these, 34 patients (82.9%) had abnormal results. The commonest abnormality was isolated HPT: 11 patients (26.8%) had heat hypoalgesia and 18 (43.9%) had heat hyperalgesia, whereas only 2 (4.9%) of the healthy control patients had hyperalgesia on testing. Multiple sensory modalities were found to be abnormal in patients with erythromelalgia, with the commonest clinical abnormality being isolated heat-pain abnormality. These findings lend support to the notion that neuropathy underlies the clinical diagnosis of erythromelalgia. Future studies will explore the nature of the relationship between these sensory abnormalities and the clinical features of erythromelalgia.
OBJECTIVE: To report a positive outcome using a spinal cord stimulator in the treatment of pain s... more OBJECTIVE: To report a positive outcome using a spinal cord stimulator in the treatment of pain secondary to trigeminal trophic syndrome, previously refractory to medical management. BACKGROUND: Trigeminal trophic syndrome (TTS) is an unusual consequence of injury to the trigeminal nerve, characterized by the clinical triad of unilateral trigeminal anesthesia, facial dysesthesias and non-healing skin ulcerations, especially of the lateral nasal ala. Whether ulcerations occur secondary to self-manipulation alone remains a matter of debate. Some theorize that TTS is caused by dysregulation of neurotrophic factors, with self-manipulation playing an exacerbating role. Pain associated with TTS can be extremely challenging to treat and quite debilitating. Various neurological and dermatological case reports have detailed methods of pain treatment, including oral and topical agents. Successful treatment of TTS pain with a spinal cord stimulator, however, has not been reported. DESIGN/METHODS Case Report. RESULTS: We present a 25 year old female patient who developed TTS following four microvascular decompression procedures of the trigeminal nerve for the treatment of trigeminal neuralgia. In the year following her final decompression which also included a partial sectioning of the trigeminal nerve, facial ulcers began to appear, first inside her nostril, then elsewhere in the maxillary and mandibular regions and later on her forehead. She experienced significant pruritus and dysesthesias around these ulcers, and continued to have trigeminal neuralgiform pain. She tried multiple medications with the goal of controlling her pain, with none providing sufficient relief. These included multiple antiepileptics, tricyclic antidepressants, topical medicines, and opiates. She ultimately had a cervicomedullary junction spinal cord stimulator placed which resulted in 70-80% pain reduction, enabling her to taper off all opiates. CONCLUSIONS: Cervicomedullary junction spinal cord stimulation may be a treatment option in cases of refractory pain due to trigeminal trophic syndrome. Study supported by: N/A Disclosure: Dr. Golden has nothing to disclose. Dr. Robertson has nothing to disclose. Dr. Moossy has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Garza has received personal compensation for activities with UpToDate as an author. Dr. Garza has received personal compensation in an editorial capacity for Current Neurology and Neuroscience Reports.
OBJECTIVE: To compare the sensitivity of autonomic testing with that of current consensus criteri... more OBJECTIVE: To compare the sensitivity of autonomic testing with that of current consensus criteria in a large cohort of patients with autopsy-confirmed Multiple System Atrophy (MSA). BACKGROUND: Diagnostic Consensus Criteria for MSA are widely accepted as gold standard for the diagnosis of MSA. Neurologists at Mayo rely heavily on autonomic testing in their diagnostic considerations of patients with MSA, supported by our previous work establishing high sensitivity/specificity of autonomic testing in the differentiation of MSA from other synucleinopathies. A direct comparison of the value of consensus criteria versus autonomic testing in the diagnosis of MSA is lacking. DESIGN/METHODS: 49 autopsy-confirmed cases of MSA were included. Clinical data at the time of first presentation to Mayo were reviewed and consensus criteria applied. Standardized autonomic testing was reviewed and scored using a validated composite autonomic severity score (CASS, 0-10). Results of thermoregulatory sweat testing were documented as [percnt] anhidrosis (TST, 0-100[percnt]). CASS score 蠅5 and TST-anhidrosis 蠅30[percnt] were used as criteria for autonomic failure consistent with MSA. RESULTS: Of 49 MSA cases, 28 (57[percnt]) were male. Age at presentation was 60.5±7.8 years. 67[percnt] were MSA-p. Symptoms had been present for 4.5±3.1 years, time to death from presentation was 3.4±2.1 years. Only 57[percnt] fulfilled consensus criteria for probable and 82[percnt] for possible MSA. The reasons for not meeting criteria were 1) clinically significant levodopa-response, 2) circumstances preventing an adequate levodopa trial, and 3) autonomic or motor criteria not fulfilled. In contrast, 45 patients (92[percnt]) had a CASS蠅5, and 81[percnt] had TST-anhidrosis 蠅30[percnt]. CONCLUSIONS: Our data suggest that autonomic testing can markedly increase the sensitivity of current consensus criteria and allow for increased diagnostic certainty. Future revisions to the consensus criteria may benefit from softening the requirement of levodopa responsiveness, and adding autonomic laboratory criteria. Supported by NIH (P01NS44233, U54NS065736, K23NS075141, UL1RR24150), Mayo Funds. Disclosure: Dr. Singer has received license fee payments from Jacobus Pharmaceutical. Dr. Schmeichel has nothing to disclose. Dr. Parisi has nothing to disclose. Dr. Benarroch has received personal compensation in an editorial capacity for Neurology. Dr. Fealey has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Ahlskog has nothing to disclose. Dr. Bower has nothing to disclose. Dr. Matsumoto has nothing to disclose. Dr. Low has received personal compensation for activities with Chelsea Therapeutics, Pfizer Inc., and WR Medical Electronics Company as a consultant.
Autonomic Neuroscience: Basic and Clinical, Nov 1, 2015
Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative... more Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter natural history study of the NIH-sponsored U.S. Autonomic Disorders Consortium. Methods: Patients with a clinical diagnosis of MSA were prospectively enrolled at 5 participating centers. Demographic data, clinical variables, and autonomic testing results were included. Results: One hundred and nine patients with MSA (45 women) have been enrolled. MSA-C was predominant (60 patients, 55%). Mean age at symptom onset was 56.5 ± 8.8 and at enrollment was 61.2 ± 8.04 years old. MiniMental score was 28.9 ± 1.4 indicating normal cognition. Both the E:I ratio (1.09 ± 0.08) and the Valsalva ratio (1.24 ± 0.28) were low, indicating cardiovagal impairment. In the supine position, blood pressure (SBP/DBP)was 146 ± 24/82 ± 15mmHg, and heart rate (HR) was 74 ± 11 bpm (mean± SD). After 3-min head-up tilt, BP fell to 111 ± 23/67 ± 16mmHg andHR increased to 82 ± 11 bpm. Plasma norepinephrine level while supine was 278 ± 163 pg/ml and increased only to 409 ± 229 pg/ml upon head-up tilt indicating impaired baroreflex-mediated sympathetic activation. UPSIT score was 32.3 ± 4.1 indicating preserved olfaction. Symptoms suggesting REM behavior disorder were reported by 67%. Conclusions: Our results confirm that: i) symptom onset in MSA is remarkable consistent at 56 years; ii) overt cognitive impairment is not a typical feature; iii) sympathetic and cardiovagal deficits are present; iv) olfaction is preserved, and; v) sleep behavioral problems are frequent. Longitudinal evaluation of these patients will provide additional information on the natural history of the disease.
OBJECTIVE To assess the long-term neurological safety of tanezumab, a monoclonal antibody against... more OBJECTIVE To assess the long-term neurological safety of tanezumab, a monoclonal antibody against nerve growth factor. METHODS Patients with osteoarthritis of the hip or knee received stable doses of oral nonsteroidal anti-inflammatory drugs (NSAIDs) before study entry and during a ≤ 37-day screening period. Patients were randomized 1:1:1 to double-dummy tanezumab (2.5 mg or 5 mg, subcutaneous every 8 weeks) or oral NSAIDs (twice-daily) for 56 weeks, with a 24-week follow-up. Neurological safety evaluation focused on peripheral and sympathetic adverse events (AEs), neurologic examinations, and consultations with blinded, external diagnostic reviews. RESULTS During the treatment period, 6.2%, 9.0%, and 4.6% of patients experienced AEs of abnormal peripheral sensation (APS) in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. Hypoesthesia, paresthesia, and carpal tunnel syndrome were the most common AEs of APS. Clinically significant worsening on examination occurred in <1% in any treatment group at the last study assessment. Diagnoses following external neurological consultation included mononeuropathy (1.3%, 2.1%, and 1.0%), radiculopathy (0.9%, 0.4%, and 0.5%), and polyneuropathy (0.3%, 0.5%, and 0%) in tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. AEs potentially associated with sympathetic neuropathy were reported for 1.8%, 2.3%, and 2.9% of patients in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. No patient was diagnosed with sympathetic neuropathy. CONCLUSION Tanezumab had an increased incidence of AEs of APS versus NSAID; these were typically mild/moderate in severity, resolved during the study, and rarely resulted in discontinuation. Tanezumab was not associated with peripheral neuropathy and did not adversely affect the sympathetic nervous system. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT02528188 (https://clinicaltrials.gov/ct2/show/NCT02528188).
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