The natural history and long-term outcome of 57 limb sarcoidosis neuropathy cases.

Fifty-seven patients with biopsy-proven sarcoidosis causing limb neuropathy were reviewed in order to delineate the characteristic symptoms, impairments, disability, course, outcome and response to corticosteroid treatment of limb sarcoid neuropathy. Typically the neuropathy had a definite date of symptomatic onset. Prominent were positive neuropathic sensory symptoms (P-NSS), especially pain, overshadowing weakness and sensory loss. P-NSS were the main cause of disability. Almost always the pattern was asymmetric and not length-dependent (unlike distal polyneuropathy). We inferred (from kind and distribution of symptoms, signs and electrophysiologic and other test results) that the pathologic process was focal or multifocal, involving most classes of nerve fibers and variable levels of proximal to distal levels of roots and peripheral nerves. Additional features aiding in diagnosis were: systemic symptoms such as fatigue, malaise, arthralgia, fever and weight loss; involvement of multiple tissues (i.e. skin, lymph nodes and eye); the patterns of neuropathy; MRI features; and ultimately tissue diagnosis. Axonal degeneration predominated, although an acquired demyelinating process was observed in 3 patients. For most cases, the disease had a chronic, monophasic course. MRI studies done in later years of affected neural structures were helpful in identifying leptomeningeal thickening, hilar adenopathy; and enlargement and T2 enhancement of nerve roots, plexuses, and limb nerves. Corticosteroid treatment appeared to ameliorate symptoms more than impairments. Several variables were associated with neuropathic improvement: CSF pleocytosis, short duration between symptom onset and treatment, and a higher grade of disability at first evaluation-a possible rationale for future earlier diagnosis and treatment.

Diagnosis of progressive multifocal leukoencephalopathy by brain biopsy with biotin labeled DNA:DNA in situ hybridization.

DNA:DNA in situ hybridization using a cloned JC virus (JCV) DNA probe labeled with biotin confirmed the presence of JCV DNA in formalin-fixed, paraffin-embedded brain biopsies from four cases of progressive multifocal leukoencephalopathy (PML). Only small pieces of tissue were available in each case. Detection of the JC DNA:DNA hybrids was carried out by affinity cytochemistry. JCV DNA was identified predominantly in the nuclei of interfascicular oligodendrocytes in demyelinated areas of the biopsies. JC virus was isolated from one case, and the diagnosis of PML was substantiated in all cases by electron microscopic identification or immunocytochemical labeling of JC viral antigen. In situ hybridization using a biotin labeled JCV DNA probe is a specific, sensitive and convenient method for confirming the diagnosis of PML in suspected cases evaluated by brain biopsy.

Administration of recombinant human leukocyte alpha 2-interferon in patients with amyotrophic lateral sclerosis.

Recombinant leukocyte alpha 2-interferon (with greater than 98% purity) was evaluated in a pilot treatment in six patients with amyotrophic lateral sclerosis and one patient with slowly progressive postpoliomyelitis motor neuron disease. Interferon, administered subcutaneously in doses of 2 million units three times per week for four months, was ineffective in improving, arresting, or slowing the pace of progression in all the patients who were followed up for ten to 14 months after the end of therapy.

Quantitation of 14-3-3 and neuron-specific enolase proteins in CSF in Creutzfeldt-Jakob disease.

CSF 14-3-3 and neuron-specific enolase (NSE) proteins were quantitated from patients who had Creutzfeldt-Jakob disease (CJD) or other rapidly dementing disorders initially considered to be CJD. Thirty-one patients were diagnosed as having CJD among 152 studied. CSF 14-3-3 values more than 8 ng/mL correlated with CJD. CSF NSE values less than 30 ng/mL and 14-3-3 values less than 8 ng/mL made a diagnosis of CJD unlikely, but did not exclude it.

Progressive multifocal leukoencephalopathy: JC virus detection by in situ hybridization compared with immunohistochemistry.

In four cases of progressive multifocal leukoencephalopathy (PML), we compared biotin-labeled DNA:DNA in situ hybridization with peroxidase immunohistochemistry for the detection of JC virus (JCV). The localization of JCV DNA and JCV capsid protein was compared in formalin-fixed, paraffin-embedded brain tissues. Infected oligodendrocytes showed both JCV DNA and JCV protein. However, bizarre astrocytes demonstrated JCV capsid protein less often than JCV DNA. In situ hybridization with a biotinylated probe was as sensitive and specific as immunohistochemistry for diagnosis on formalin-fixed tissue. The presence of both JCV DNA and viral capsid protein in bizarre astrocytes suggests that these cells are neither truly transformed nor permissively infected, but are distinctively altered by JCV.

Traumatic occlusion of one limb of an intracranial arterial fenestration: an uncommon cause of stroke.

Three weeks after an automobile accident, a 35-year-old man experienced left throat and neck pain, numbness of the left face and tongue, dysphagia, left arm pain and weakness, and left miosis. At age 27, he had suffered an aneurysmal subarachnoid hemorrhage. Angiography at that time had also demonstrated a fenestration of the left intracranial vertebral artery. At the time of the second presentation, angiography showed that one of the limbs of the fenestration had become occluded. Although the vast majority of intracranial arterial fenestrations are asymptomatic, occlusion of one of the limbs of a fenestration may be the cause of stroke.

AIDS-associated progressive multifocal leukoencephalopathy (PML): comparison to non-AIDS PML with in situ hybridization and immunohistochemistry.

We studied brain sections from 10 patients with the acquired immunodeficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML) by in situ hybridization with a biotin-labeled JC virus (JCV) DNA probe and by immunohistochemistry using antibody against the JCV capsid antigen. We compared the results with brain sections studied in the same fashion from 10 PML patients without AIDS. The pathology of JCV infection in AIDS was similar to non-AIDS PML except for minor differences in degree. AIDS-associated pathologic material showed a greater tendency toward necrosis and a higher density of JCV-infected cells. Replication of JCV was restricted to glial cells in all tissue studied. Bizarre astrocytes were less frequent in the AIDS patients, and perivascular inflammatory cells were more frequent. We could not demonstrate JCV in macrophages or microglial cells known to harbor HIV infection. In situ hybridization with nonradioactive probes serves as a useful technique for the confirmation of PML in AIDS.

Nonradioactive in situ hybridization in progressive multifocal leukoencephalopathy.

Biotinylated DNA:DNA in situ hybridization was used for determining the presence of JC virus in brain tissues of 67 patients thought to have progressive multifocal leukoencephalopathy. Sixty patients had acquired immunodeficiency syndrome (AIDS) or other illnesses that decreased the cell-mediated immunity. Two patients had no underlying disease, and five others had chronic illnesses not typically associated with reduced cell-mediated immunity. In situ hybridization with biotinylated probe provides specificity and ease of interpretation. The presence of virus can be correlated at the single-cell level with attendant pathologic changes in oligodendrocytes and astrocytes. Not only archival tissue but also tiny fragments of brain biopsy material can be evaluated successfully. Quantifying the technique suggests that the nucleus of a cell labeling for JC virus DNA averages 1,000 copies of replicating genome. Identification of an infected cell is pathologically significant even when only a few such cells are present in a biopsy specimen. Biotinylated DNA or RNA probes are equally effective in identifying infected cells. In situ hybridization will likely continue to be a useful adjunctive procedure for the evaluation of brain tissue from patients suspected of having progressive multifocal leukoencephalopathy.

Outcome of chronic idiopathic meningitis.

OBJECTIVE: To record long-term follow-up data on patients with chronic idiopathic meningitis. DESIGN: We retrospectively reviewed the outcome of 49 patients who were examined at the Mayo Clinic between 1978 and 1990. MATERIAL AND METHODS: For all patients, symptoms, signs, laboratory values, results of imaging studies, findings on biopsies, results of any empiric treatment, and results of autopsy, if applicable, were assessed. Some of these findings were stratified on the basis of good versus poor outcome of the patients and were analyzed statistically. RESULTS: Of the 49 patients who fulfilled the criteria for chronic idiopathic meningitis, 10 had a cause identified after repeated studies, brain biopsy, or autopsy (8 of these had a neoplasm). Of 21 brain biopsies, 5(24%) yielded a diagnosis. Follow-up of the 39 undiagnosed cases showed that 33 (85%) had a good outcome despite an often prolonged illness. Two patients (5%) died of the meningeal process. Of the eight patients treated empirically with antituberculous medications, none responded. Corticosteroid therapy was effective in 52% of the patients thus treated, but it did not influence the outcome. CONCLUSION: In this study, 85% of undiagnosed cases of chronic meningitis were benign. No clinical or laboratory findings predicted those patients who had a fatal outcome. In our study population, the most useful empiric therapy was corticosteroids rather than antituberculous medications.

Herpes zoster-associated meningoencephalitis in patients with systemic cancer.

We reviewed the experience at the Mayo Clinic with neurologic complications related to herpes zoster in patients with systemic cancer. Aside from pain, the most common neurologic complication was zoster-associated meningoencephalitis, which occurred in 9 of 1,125 patients. In these nine patients, the most common underlying malignant lesions were chronic lymphocytic leukemia and lymphoma. All patients in whom meningoencephalitis developed had trigeminal zoster or disseminated zoster. The primary neurologic symptoms were headache, confusion, and somnolence. Nuchal rigidity and fever were uncommon. The response to treatment with acyclovir was generally favorable.

Cidofovir treatment of progressive multifocal leukoencephalopathy in a patient receiving highly active antiretroviral therapy.

Progressive multifocal leukoencephalopathy (PML), a frequently fatal demyelinating disease caused by JC virus, occurs as an opportunistic infection in patients with acquired immunodeficiency syndrome. Curative therapy has been elusive, but recent reports suggest its improvement after institution of highly active antiretroviral therapy (HAART). We describe a case of PML that developed 6 months after the patient, a 55-year-old man, began to receive HAART. The PML progressed despite good virologic and immunologic response to HAART. Substantial symptomatic and radiographic improvement occurred after the addition of cidofovir to the treatment regimen. We reviewed the scientific literature on this rare occurrence of PML after institution of HAART and describe the patient characteristics, potential pathogenesis, and therapeutic options, including the successful use of cidofovir as an adjunctive agent.

Progressive multifocal leukoencephalopathy: a review of the pathology and pathogenesis.

Progressive multifocal leukoencephalopathy is an important viral opportunistic infection of oligodendrocytes leading to direct demyelination. Virus is likely disseminated to the brain via the blood. However, the timing of that dissemination with relationship to clinical disease is unknown. Important clues about viral pathogenesis have been learned by applying molecular in situ techniques to diseased brain. The oligodendrocyte is the primary target for JC virus infection, and its death is the primary reason for demyelination. Bizarre astrocytes show limited viral DNA replication but are abortively infected. Although lymphoid organs can be infected by JC virus, there is no definitive evidence that lymphoid cells carry virus into the brain at the time of immunosuppression. JC virus may be reactivated from a latent state in both the brain and in non-central nervous system (CNS) organs at the time of immunosuppression, leading to clinical disease. Future sensitive in situ studies will likely resolve controversies about pathogenesis.

Progressive multifocal leukoencephalopathy in AIDS: a clinicopathologic study and review of the literature.

We reviewed the clinical, radiographic, and pathologic features of 15 patients with the acquired immune deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). Brain tissue from 10 autopsy and 6 biopsy specimens was studied using: in situ hybridization (ISH) for JC virus (JCV), immunohistochemistry for human immunodeficiency virus (HIV) p24 antigen, and electron microscopy. Thirteen patients presented with focal neurologic deficits, while 2 presented with a rapid decline in mental status. PML was commonly the initial opportunistic infection of AIDS and produced hemiparesis, dementia, dysarthria, cerebellar abnormalities, and seizures. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions, and often showed multifocal areas of PML. CD4+ T-cell counts were uniformly low (mean 84/mm3), except in 1 patient who improved on 3'-azido-3'-deoxythymidine (AZT). PML involved the cerebral hemispheres, brain stem, cerebellum, and cervical spinal cord. The distribution of brain involvement was consistent with hematogenous dissemination of the virus. In 2 brain specimens, multiple HIV-type giant cells were present within the regions involved by PML. When co-infection by HIV and papovavirus was present, PML dominated the pathological picture. ISH for JCV showed virus in the nuclei of oligodendrocytes and astrocytes. Occasionally there was staining for JCV in the cytoplasm of glial cells and in the neuropil, the latter possibly a correlate of papovavirus spread between myelin sheaths, as seen by electron microscopy. ISH demonstrated more extensive foci of PML than did routine light microscopy.

Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues.

OBJECTIVE: To report the clinical phenotype and outcome of isolated paraneoplastic myelopathy. METHODS: We systematically reviewed clinical, serologic, and MRI data for 31 patients (20 female) who presented with an isolated myelopathy and coexisting cancer: carcinoma (lung, 9; breast, 7; kidney, 2; thyroid, 2; ovary/endometrium, 2), melanoma (2), or other cancer (3), or a paraneoplastic autoantibody with strong cancer association (amphiphysin-immunoglobulin G [IgG], 9; collapsin response-mediator protein 5-IgG, 9; Purkinje-cell cytoplasmic autoantibody type 1, 2; antineuronal nuclear autoantibody [ANNA]-1, 1; ANNA-3, 1). RESULTS: Of 31 patients who presented with a progressive myelopathy, symptom onset was subacute in 16 (52%). The median age was 62 years. CSF abnormalities included elevated protein (>45 mg/dL), 22; pleocytosis, 15; excess oligoclonal bands (normal <4), 7. MRI cord abnormalities identified in 20 patients were longitudinally extensive (>3 vertebral segments), 14; symmetric tract or gray matter-specific signal abnormality, 15 (enhancing in 13). Myelopathy preceded cancer diagnosis in 18 patients (median interval 12 months; range 2-44). After myelopathy onset, 26 patients underwent oncologic treatment, immunosuppressive treatment (median delay to commencing immunotherapy 9.5 months [range 1-54]), or both; only 8 improved (31%). At last neurologic evaluation (median interval after onset 17 months; range 1-165 months), 16 patients (52%) were wheelchair-dependent (median time from onset to wheelchair 9 months [range 1-21]). Ten patients died after a median of 38 months from symptom onset (range 7-152). CONCLUSION: Symmetric, longitudinally extensive tract or gray matter-specific changes on spinal MRI should raise suspicion for a paraneoplastic myelopathy. Resulting disability is often severe. Only a minority of patients improve with treatment.

MR imaging of central nervous system Whipple disease: a 15-year review.

CNS WD is fatal if antibiotics are not begun early, but knowledge regarding the variety of presentations on MR imaging is limited. In order to more effectively recognize this entity on MR imaging, the Mayo Clinic medical records were reviewed for subjects diagnosed with CNS WD from 1992-2006 who had also undergone MR imaging of the neuraxis. Seven subjects were identified and their imaging findings were reviewed by the authors. Four of 7 had head MR imaging findings indicative of WD. Two subjects demonstrated high T2 signal within the corticospinal tracts. CNS WD may demonstrate high T2 signal with minimal enhancement and no restricted diffusion, primarily in the midline of the midbrain, hypothalamus, and mesial temporal lobes and occasionally the corticospinal tracts. MR imaging may also be normal. Radiologists should be aware of these presentations and be prepared to mention CNS WD as a diagnostic possibility since early antibiotic therapy may significantly impact morbidity and mortality.

Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside.

This open label study determined the outcome of non-AIDS progressive multifocal leukoencephalopathy patients treated with a standard dose of intravenous cytosine arabinoside. Nineteen patients with PML proven by brain biopsy or spinal fluid polymerase chain reaction were treated with intravenous cytosine arabinoside 2 mg/kg per day for 5 days and followed for neurologic outcome by neurologic examination and MRI scanning. Seven of 19 PML patients treated with cytosine arabinoside intravenously improved neurologically. The range of follow-up for these patients was 2.0 to 4.5 years. All were left with neurologic deficits but were functionally improved, and 6 of 7 were able to independently carry out the activities of daily living. Twelve PML patients showed no evidence of response and died rapidly of their disease after treatment (range, 8 days to 6 months). All who survived their neurologic disease recovered from treatment-induced pancytopenia. Cytosine arabinoside given intravenously to non-AIDS PML patients in this small study was associated with a 36% chance of developing stabilization at 1 year. Treatment was associated with significant bone marrow toxicity. The improvement in MRI scan changes in those patients who responded took 6 weeks or longer.

Paradoxical postural headaches in cerebrospinal fluid leaks.

Two patients with cerebrospinal fluid (CSF) leak, one at the level of fourth thoracic spine and another with undetermined level of leak, presented with paradoxical postural headaches in that the headaches were present when in a horizontal position and resolved if the patients were upright. One patient improved spontaneously and the other responded to a targeted epidural blood patch. Paradoxical postural headache is yet another headache type that can be associated with CSF leak and CSF volume depletion. Its mechanism is uncertain, but it could be related to congestion and dilatation of cerebral venous sinuses and large veins.