Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic implications.

OBJECTIVE: To characterize the neuropathologic features of neuromyelitis optica (NMO) at the medullary floor of the fourth ventricle and area postrema. Aquaporin-4 (AQP4) autoimmunity targets this region, resulting in intractable nausea associated with vomiting or hiccups in NMO. METHODS: This neuropathologic study was performed on archival brainstem tissue from 15 patients with NMO, 5 patients with multiple sclerosis (MS), and 8 neurologically normal subjects. Logistic regression was used to evaluate whether the presence of lesions at this level increased the odds of a patient with NMO having an episode of nausea/vomiting. RESULTS: Six patients with NMO (40%), but no patients with MS or normal controls, exhibited unilateral or bilateral lesions involving the area postrema and the medullary floor of the fourth ventricle. These lesions were characterized by tissue rarefaction, blood vessel thickening, no obvious neuronal or axonal pathology, and preservation of myelin in the subependymal medullary tegmentum. AQP4 immunoreactivity was lost or markedly reduced in all 6 cases, with moderate to marked perivascular and parenchymal lymphocytic inflammatory infiltrates, prominent microglial activation, and in 3 cases, eosinophils. Complement deposition in astrocytes, macrophages, and/or perivascularly, and a prominent astroglial reaction were also present. The odds of nausea/vomiting being documented clinically was 16-fold greater in NMO cases with area postrema lesions (95% confidence interval 1.43-437, p = 0.02). CONCLUSIONS: These neuropathologic findings suggest the area postrema may be a selective target of the disease process in NMO, and are compatible with clinical reports of nausea and vomiting preceding episodes of optic neuritis and transverse myelitis or being the heralding symptom of NMO.

Absence of cortical demyelination in neuromyelitis optica.

OBJECTIVE: To asses the presence of cortical demyelination in brains of patients with neuromyelitis optica (NMO). NMO is an autoimmune inflammatory demyelinating disease that specifically targets aquaporin-4-rich regions of the CNS. Since aquaporin-4 is highly expressed in normal cortex, we anticipated that cortical demyelination may occur in NMO. METHODS: This is a cross-sectional neuropathologic study performed on archival forebrain and cerebellar tissue sections from 19 autopsied patients with a clinically and/or pathologically confirmed NMO spectrum disorder. RESULTS: Detailed immunohistochemical analyses of 19 archival NMO cases revealed preservation of aquaporin-4 in a normal distribution within cerebral and cerebellar cortices, and no evidence of cortical demyelination. CONCLUSIONS: This study provides a plausible explanation for the absence of a secondary progressive clinical course in NMO and shows that cognitive and cortical neuroimaging abnormalities previously reported in NMO cannot be attributed to cortical demyelination. Lack of cortical demyelination is another characteristic that further distinguishes NMO from MS.

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.

OBJECTIVE: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. METHODS: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. RESULTS: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). CONCLUSIONS: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in cerebrospinal fluid differ in multiple sclerosis and Devic's neuromyelitis optica.

Matrix metalloproteinases (MMPs) are increased in the CSF of patients with multiple sclerosis. Devic's neuromyelitis optica (DNO) is a demyelinating syndrome that involves the optic nerve and cervical cord but differs pathologically from multiple sclerosis. Therefore, we hypothesized that the type of inflammatory reaction that causes MMPs to be elevated in multiple sclerosis would be absent in patients with DNO. CSF was collected from 23 patients with relapsing-remitting or secondary progressive multiple sclerosis, all of whom were experiencing acute symptoms, from seven patients with DNO, and from seven normal volunteers. Diagnoses were made according to current criteria on the basis of clinical manifestations, imaging results and CSF studies. IgG synthesis was increased in the CSF of multiple sclerosis patients but not in that of DNO patients. Zymography, reverse zymography and ELISA (enzyme-linked immunosorbent assay) were used to measure gelatinase A (MMP-2), gelatinase B (MMP-9) and tissue inhibitors of metalloproteinases (TIMPs). Zymograms showed that multiple sclerosis patients had elevated MMP-9 compared with DNO patients and controls (P: < 0.05). TIMP-1 and TIMP-2 levels were similar in all three groups. We conclude that multiple sclerosis patients have higher MMP-9 levels in the CSF than patients with DNO, which supports the different pathological mechanisms of these diseases.

The ALS Patient Care Database: insights into end-of-life care in ALS.

OBJECTIVE: To study clinical practices and patient outcomes near the end of life in amyotrophic lateral sclerosis (ALS). BACKGROUND: Patients, families, and healthcare providers face several dilemmas in selecting and delivering care near the end of life in ALS. Published data on clinical practices and their benefits during end-of-life care for ALS patients consist of anecdotal reports based on small case series or individual case reports. METHODS: Data were obtained from 1014 American and Canadian patients with ALS who died while participating in a large observational registry (the ALS Patient Care Database) during the past four years. Following death, a caregiver or family member provided data for each patient using a standard questionnaire. Data were principally generated through American and Canadian ALS multidisciplinary centers of excellence. RESULTS: Most patients died peacefully (90.7%) and 62.4% died in a hospice-supported environment. Advance directives were in place for 88.9% of patients and were followed in 96.8%. Among the 67 patients who exhibited distress in the dying process, symptoms included breathing difficulties (82.1%), fear/anxiety (55.2%), pain (23.9%), insomnia (14.9%), and choking (14.93%). Oxygen was given to 52.6% of patients, and pain medications were given to 74%. CONCLUSION: These data suggest that palliative care at the end of life was relatively well managed for most patients with ALS who participated in this study; nevertheless, several opportunities for improvement were identified.

Devic's neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine.

Seven newly diagnosed patients with Devic's neuromyelitis optica were treated with long-term prednisone and azathioprine, and were followed every 2 months for at least 18 months. Their Expanded Disability Status Scale score improved significantly (mean at baseline, 9; mean at 18 months, 3; p < 0.005), and no relapses occurred for more than 18 months. Multicenter controlled studies are needed to prove the efficacy of this therapeutic regimen.

Fulminant demyelinating neuropathy mimicking cerebral death.

Guillain-Barré syndrome can very rarely present with acute quadripares and cranial nerve involvement resembling a locked-in state. We describe a very unusual case of fulminant neuropathy in a child who was previously exposed to vincristine. The clinical picture resembled brain death; however, electrodiagnostic studies led to the diagnosis of a peripheral neuropathy. Serial electrodiagnostic studies and pathologic findings confirmed demyelination.

Cluster of wound botulism in California: clinical, electrophysiologic, and pathologic study.

Over a period of 15 months we have seen 6 patients with long-standing history of subcutaneous heroin injections who experienced acute blurred vision, dysphagia, dysarthria, and generalized weakness. Decreased or absent deep tendon reflexes, pupillary abnormalities, incremental responses to fast repetitive nerve stimulation, and positive serology for Clostridia botulinum toxin A were found, but not in all cases. Muscle biopsies showed variable signs of neurogenic atrophy. In vitro electrophysiology studies revealed decreased end-plate potentials quantal content, confirming the presynaptic nature of the disorder. Mechanical ventilation was required in 5 patients. Half of the patients were treated with polyvalent antitoxiin. Prognosis was favorable, though recovery was slow. In conclusion, acute bulbar weakness with visual symptoms in patients with subcutaneous heroin abuse strongly suggets the possibility of wound botulism. High diagnostic suspicion combined with histology and in vitro electrophysiology confirmation of presynaptic failure, especially in seronegative cases, may significantly improve morbidity.

Quantitative measurement of muscle strength in the mouse.

We have designed a special dynamometer for measuring mouse forelimb muscle strength and endurance. The device exploits a mouse's tendency to grasp a horizontal metal bar while suspended by its tail. A threshold value for the magnitude and duration of force that the mouse can exert is obtained by first allowing the animal to grasp the bar and then applying a steadily increasing downward force to the opposite end of a cable to which the mouse attaches. The bar is attached to a force transducer and pen recorder to produce a permanent record of the force produced by the mouse. Test results show that this dynamometer provides quantitative measurements of muscle strength and endurance in the mouse. Comparisons between experimental groups of normal and wobbler mice, a model for lower motor neuron disease, show that both the force exerted by the animals (muscle strength), and the duration of the pull (endurance), can be quantified and statistically analyzed. This technique can be used as an assay for quantitating the effects of in vivo drug treatments on murine neuromuscular disorders.

Neurologic manifestations of intravascular lymphomatosis.

Intravascular lymphomatosis is a rare fatal neoplasm characterized by malignant cells of lymphocytic lineage producing vascular occlusions. The cerebral vasculature is particularly affected. Two patients seen at our institution presented with progressive neurologic deficits including dementia, hemiparesis and myelopathy. Review of an additional 64 reported cases with neurologic involvement indicates that patients developed intermittent fevers, an encephalopathy ranging from acute disorientation to rapidly progressive dementia, and focal signs such as hemiparesis and myelopathy. Common laboratory abnormalities include elevated cerebrospinal fluid protein and a lymphocytic pleocytosis, elevated blood erythrocyte sedimentation rate and serum lactate dehydrogenase. Malignant cells are rarely seen in cerebrospinal fluid, blood or bone marrow. Neuroimaging is usually abnormal with parenchymal lesions seen on cerebral tomography and magnetic resonance imaging along with an occasional meningeal pattern of contrast enhancement. Treatment with corticosteroids, chemotherapy, radiation therapy, or plasmapheresis provided limited benefit. Intravascular lymphomatosis should be considered in the differential diagnosis of unexplained progressive encephalopathy with superimposed focal deficits.

Devic's neuromyelitis optica: a clinicopathological study of 8 patients.

We report the clinical, imaging, and laboratory features of 8 patients with Devic's neuromyelitis optica. All patients had severe myelopathy and optic neuritis. In no patient was the brain, the brainstem, or the cerebellum affected, even after several years of disease. Various immunosuppressive treatments failed to benefit the patients, 5 of whom died. Autopsies of these 5 patients demonstrated a severe necrotizing myelopathy with thickening of blood vessel walls and no lymphocyte infiltrates. In the appropriate clinical setting, the lack of white matter abnormalities demonstrated by magnetic resonance imaging of the head facilitates the recognition of Devic's syndrome during life. Inasmuch as Devic's myelopathy is necrotizing, rather than demyelinating, the prognosis of this syndrome is poor.

Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events.

OBJECTIVE: A study was undertaken to determine whether cases of parainfectious-associated transverse myelitis (TM) and multiple sclerosis-associated TM could be distinguished on the basis of clinical criteria, radiologic features, or cerebrospinal fluid examination. A secondary objective was to determine the incidence of TM in a US population. DESIGN: A retrospective analysis of 33 cases was conducted. Cases were classified as being related to parainfectious multiple sclerosis, or spinal cord ischemia, or idiopathic. SETTING: All cases occurring in the Albuquerque, NM, area from 1960 through 1990 were reviewed. The population base was 500,000. OUTCOME MEASURES: Clinical presentation, radiologic features, cerebrospinal fluid, recovery of ambulation and bladder function, and recurrence rates were compared. RESULTS: Thirty-three patients satisfied study criteria, corresponding to an incidence of 4.6 per million per year. Forty-five percent of these cases were categorized as parainfectious, 21% as associated with multiple sclerosis, 12% as associated with spinal cord ischemia, and 21% as idiopathic. Patients with parainfectious TM suffered from spinal shock more frequently than did those with multiple sclerosis-associated TM. Patients with parainfectious TM showed evidence of spinal cord swelling, whereas patients with multiple sclerosis-associated TM had spinal cord plaques on magnetic resonance images but none showed swelling. Oligoclonal bands were absent in patients with parainfectious TM and present in three of five patients with multiple sclerosis-associated TM. CONCLUSIONS: Parainfectious TM may be distinguishable from that associated with multiple sclerosis on the basis of presentation, findings on imaging, and the presence of cerebrospinal fluid oligoclonal bands.

Progesterone but not estrogen depolarizes natural killer cells.

Natural killer (NK) cell tumoricidal and antimicrobial activities can be rapidly modulated by molecules that interact with membrane receptors. The discovery of NK cell depolarization induced by steroid-like Na+ channel agonists prompted a study of purified human NK cell excitability to a variety of steroids. Progesterone, but not estrogen, depolarized NK cells with concentration and time dependency. Excitability was measured by using flow cytometry and the anionic voltage-sensitive dye oxonol. Preincubation with the Na+ channel antagonist tetrodotoxin or removal of the extracellular Na+ blocked the response. Progesterone may rapidly change membrane potential, and eventually function, by acting on putative NK plasma membrane receptors coupled to Na+ conductances.

Castleman's disease in POEMS syndrome with elevated interleukin-6.

POEMS syndrome is a rare multisystem affliction known for its signs, from which it also takes its acronym name "peripheral neuropathy, organomegaly, endocrinopathy, monoclonal (M) protein, and skin lesions." Our study chronicles the course of this syndrome in a young woman with Castleman's disease (angiofollicular lymph node hyperplasia). Cerebrospinal fluid (CSF) and serum interleukin-6 (IL-6) levels were abnormally elevated at various times during a 9-month period. The authors conclude that the plasma cell dyscrasia associated with the POEMS syndrome of this patient was Castleman's disease. Elevation of serum IL-6 levels might contribute to the pathogenesis of the POEMS syndrome.

Muscle lactate dehydrogenase activity is decreased in murine motor neuron disease.

Lactic dehydrogenase (LDH) activity was examined in affected skeletal muscles of the wobbler mouse, a murine model in which denervation follows degeneration of spinal cord motoneurons. Average biceps brachii LDH activity was reduced at 7 and 15 but not at 3 postnatal weeks. These results demonstrate a progressive alteration in muscle energy metabolism in a natural model of motor neuron disease.

Method to improve the sensitivity of flow cytometric membrane potential measurements in mouse spinal cord cells.

We have developed a technique to improve the sensitivity of relative membrane potential measurements in mouse spinal cord cells using the fluorescent, anionic, voltage sensitive dye, DiBa-C4(3) (Oxonol) and flow cytometry. In order to attribute cellular fluorescence primarily to membrane potential, signal variability due to cell size and shape was reduced by dividing the log fluorescence signal from each cell by either its log forward angle light scatter or log side scatter signals. The use of these ratios in place of log oxonol fluorescence reduced the coefficient of variation of the distributions while leaving the changes in mean fluorescence largely unaffected. Kolmogorov-Smirnov analysis of pre- vs. postkainate stimulation (an excitatory amino acid) showed improved sensitivity of the assay with the use of this ratio technique.

Neoplastic angioendotheliomatosis.

A 60-year-old white man presented with aphasia, seizures, paraparesis, and incontinence. His serologic and hematologic profiles were unremarkable. His cerebrospinal fluid showed pleocytosis, increased daily central nervous system IgG synthesis, increased myelin basic protein, and negative cytology and cultures. Cerebral computed tomography exhibited multiple areas of hypodensity but spinal computed tomography and myelography showed no abnormalities. Cranial and spinal magnetic resonance imaging revealed areas of increased signal on T2-weighted images. The use of gadolinium-pentetic acid on T1-weighted images delineated smaller areas of cortical enhancement with surrounding rim of decreased signal. Brain biopsy showed intravascular malignant cells positive for leukocyte common antigen and B-cell markers. The diagnosis was neoplastic angioendotheliomatosis (intravascular lymphomatosis). To our knowledge, this is the first report on the use of both cranial and spinal magnetic resonance imaging in this condition.