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.

The utility of computerized neuropsychological assessment of cognitive dysfunction in patients with relapsing-remitting multiple sclerosis.

Traditional paper-and-pencil neuropsychological batteries used to document cognitive deficits in multiple sclerosis (MS) patients lack timing precision. This makes it difficult to accurately measure psychomotor slowing, a central cognitive symptom of MS. Additionally, traditional batteries lack multiple alternate forms necessary to control for practice effects when assessing cognition over time. Finally such batteries are lengthy and expensive. Computerized neuropsychological batteries address many of these shortcomings. They measure response time more precisely, require less administration time, include alternate forms, and are ideal for rapid screening/triage. Although there are normative data on the reliability and validity of computerized measures, there have been no controlled validation studies with MS patients. The current study was designed to validate a computerized neuropsychological battery (ANAM) for use with relapsing-remitting (RR) MS patients. Prior to initiation of interferon-beta-1a (Avonex) treatment, subjects participated in a neuropsychological evaluation consisting of traditional and computerized measures. Moderate-to-high correlations were found between computerized and traditional measures. Computerized tests accurately predicted performance on key traditional tests. The battery was also concordant with traditional measures in identifying RR MS patients with and without neurocognitive impairment. Findings are discussed with respect to increased accuracy and accessibility of neuropsychological evaluations for MS patients.

Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.

BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. RESULTS: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.

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.

Immunoconjugates of geldanamycin and anti-HER2 monoclonal antibodies: antiproliferative activity on human breast carcinoma cell lines.

BACKGROUND: HER2 is a membrane receptor whose overexpression is strongly associated with poor prognosis in breast carcinomas. Inhibition of HER2 activity can reduce tumor growth, which led to the development of Herceptin, an anti-HER2 monoclonal antibody (MAb) that is already in clinical use. However, the objective response rate to Herceptin monotherapy is quite low. HER2 activity can also be inhibited by the highly cytotoxic antibiotic geldanamycin (GA). However, GA is not used clinically because of its adverse toxicity. Our purpose was to enhance the inhibitory activity of anti-HER2 MAb by coupling it to GA. METHODS: We synthesized 17-(3-aminopropylamino)GA (17-APA-GA) and conjugated it to the anti-HER2 MAb e21, to form e21 : GA. The noninternalizing anti-HER2 MAb AE1 was used as a control. Internalization assays and western blot analyses were used to determine whether the anti-HER2 MAbs and their immunoconjugates were internalized into HER2-expressing cells and reduced HER2 levels. All statistical tests were two-sided. RESULTS: The immunoconjugate e21 : GA inhibited the proliferation of HER2-overexpressing cell lines better than unconjugated e21 (concentration required for 50% inhibition = 40 versus 1650 microg/mL, respectively). At 15 microg/mL, e21 : GA reduced HER2 levels by 86% within 16 hours, whereas unconjugated e21, 17-APA-GA, or AE1 : GA reduced HER2 levels by only 20%. These effects were not caused by release of 17-APA-GA from the immunoconjugate because immunoconjugates containing [(3)H]GA were stable in serum at 37 degrees C. Furthermore, e21 : GA did not significantly inhibit proliferation of the adult T-cell leukemia cell line HuT102, which is HER2 negative yet highly sensitive to GA. CONCLUSIONS: Our findings suggest that conjugating GA to internalizing MAbs enhances the inhibitory effect of the MAbs. This approach might also be applied in cellular targeting via growth factors and may be of clinical interest.

Synthesis and evaluation of antiproliferative activity of a geldanamycin-Herceptin immunoconjugate.

Geldanamycin was modified with 1,4-diaminobutane to introduce a primary amine that was subsequently employed to provide a maleimide for protein linkage. Monoclonal antibody Herceptin was then derivatized to generate thiol groups that reacted with the maleimide derivative to produce the immunoconjugate. The product showed antiproliferative activity greater than native Herceptin.

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.

Growth hormone-dependent tyrosine phosphorylation of a GH receptor-associated high molecular WEIGHT protein immunologically related to JAK2.

A critical step in growth hormone (GH) signalling is the GH-induced activation of the GH receptor (GHR)-associated tyrosine kinase, JAK2. JAK2 is a 120 kD member of the Janus family of tyrosine kinases, whose other mammalian members include JAK1, JAK3, and TYK2. Using 3T3-F442A murine preadipocytes, we now report detection of a Mr approximately 170 kD protein, referred to as HMW ("high molecular weight") JAK2, that is specifically reactive in immunoprecipitation and immunoblotting experiments with three independently-derived anti-JAK2 antibodies--two directed at carboxyl-terminal regions of the molecule and one directed at the amino-terminus. Like JAK2, HMW JAK2 is tyrosine phosphorylated in response to GH treatment of cells and is coimmunoprecipitated with anti-GHR serum. Thus, HMW JAK2 is a protein not heretofore described that is immunologically related to JAK2 and is physically and functionally associated with the GHR.

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.

Neuromyelitis optica (Devic's syndrome): no association with the primary mitochondrial DNA mutations found in Leber hereditary optic neuropathy.

Devic's neuromyelitis optica is a rare syndrome characterised by the combination of acute or subacute optic neuritis and transverse myelitis, in some cases considered to be a variant of multiple sclerosis. Mutations of mitochondrial DNA (mtDNA) associated with Leber hereditary optic neuropathy (LHON) have been identified in some patients with multiple sclerosis in whom optic neuritis is a prominent early feature. Using restriction enzyme digestion of mtDNA products amplified by the polymerase chain reaction, the primary LHON mtDNA mutations at positions 3460 bp, 11,778 bp, and 14,484 bp have been excluded in four women with Devic's neuromyelitis optica. A mutation at 4160 bp associated in some LHON families with more widespread neurological disease was also not detected. It is concluded that the primary mtDNA mutations currently associated with LHON are not responsible for the prominence of optic nerve disease in Devic's neuromyelitis optica.

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.