Daniel Kremens

Topography of FUS pathology distinguishes late-onset BIBD from aFTLD-U

BackgroundMultiple neurodegenerative diseases are characterized by the abnormal accumulation of FUS protein including various subtypes of frontotemporal lobar degeneration with FUS inclusions (FTLD-FUS). These subtypes include atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), basophilic inclusion body disease (BIBD) and neuronal intermediate filament inclusion disease (NIFID). Despite considerable overlap, certain pathologic features including differences in inclusion morphology, the subcellular localization of inclusions, and the relative paucity of subcortical FUS pathology in aFTLD-U indicate that these three entities represent related but distinct diseases. In this study, we report the clinical and pathologic features of three cases of aFTLD-U and two cases of late-onset BIBD with an emphasis on the anatomic distribution of FUS inclusions.ResultsThe aFTLD-U cases demonstrated FUS inclusions in cerebral cortex, subcortical grey matter and brainstem with a predilection for anterior forebrain and rostral brainstem. In contrast, the distribution of FUS pathology in late-onset BIBD cases demonstrated a predilection for pyramidal and extrapyramidal motor regions with relative sparing of cerebral cortex and limbic regions.ConclusionsThe topography of FUS pathology in these cases demonstrate the diversity of sporadic FUS inclusion body diseases and raises the possibility that late-onset motor neuron disease with BIBD neuropathology may exhibit unique clinical and pathologic features.

N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data.

Backgound The purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine (NAC) in Parkinson’s disease (PD). Methods The overarching goal of this pilot study was to generate additional data about potentially protective properties of NAC in PD, using an in vitro and in vivo approach. In preparation for the clinical study we performed a cell tissue culture study with human embryonic stem cell (hESC)-derived midbrain dopamine (mDA) neurons that were treated with rotenone as a model for PD. The primary outcome in the cell tissue cultures was the number of cells that survived the insult with the neurotoxin rotenone. In the clinical study, patients continued their standard of care and were randomized to receive either daily NAC or were a waitlist control. Patients were evaluated before and after 3 months of receiving the NAC with DaTscan to measure dopamine transporter (DAT) binding and the Unified Parkinson’s Disease Rating Scale (UPDRS) to measure clinical symptoms. Results The cell line study showed that NAC exposure resulted in significantly more mDA neurons surviving after exposure to rotenone compared to no NAC, consistent with the protective effects of NAC previously observed. The clinical study showed significantly increased DAT binding in the caudate and putamen (mean increase ranging from 4.4% to 7.8%; p<0.05 for all values) in the PD group treated with NAC, and no measurable changes in the control group. UPDRS scores were also significantly improved in the NAC group (mean improvement of 12.9%, p = 0.01). Conclusions The results of this preliminary study demonstrate for the first time a potential direct effect of NAC on the dopamine system in PD patients, and this observation may be associated with positive clinical effects. A large-scale clinical trial to test the therapeutic efficacy of NAC in this population and to better elucidate the mechanism of action is warranted. Trial Registration ClinicalTrials.gov NCT02445651

Pearls & Oy-sters: Fibrocartilaginous embolism myelopathy

Fibrocartilaginous embolism myelopathy is a stroke syndrome, characterized by rapidly progressive paraplegia (hours to 2-3 days) following an episode of back pain (mostly after a minor trauma).1 CSF studies are normal and MRI shows T2 hyperintensity in the spinal cord with associated swelling, diffusion restriction, and often presence of Schmorls nodes at the level of injury.1 A 25-year-old man with no significant past medical history and an active lifestyle presented to the hospital with a complaint of bilateral lower extremity numbness and weakness. Three days prior, the patient slipped while getting out of his truck and fell into a split position. Immediately afterwards he felt a sudden pain in his left groin with associated paraesthesia and weakness initially in his left thigh. Within several hours, the weakness and paraesthesia spread over the entire left leg and 24 hours later to the right leg. He also felt his bladder was full and lost control of his flatulence. The patient was a well-developed man in mild distress with normal vital signs. On neurologic examination, mental status and cranial nerves were normal. Manual motor testing of his upper extremities was unremarkable. Testing of his lower extremities revealed increased tone bilaterally. In the right lower extremity his iliopsoas was 4/5, hamstrings were 4+/5, quadriceps were 4+/5, tibialis anterior was 5/5, and gastrocnemius was 5/5. In the left …

Schistosoma mansoni in family 5 years after safari.

To the Editor: Each year ≈350,000 Americans travel to Africa and ≈500,000 travel to Brazil and the Far East, all schistosomiasis-endemic regions. Data from the European Network on Imported Infectious Diseases Surveillance (TropNetEurop) suggest that most schistosomiasis cases imported to Europe are acquired in Africa; 80% of new cases worldwide occur in sub-Saharan Africa (1,2). Travelers to Africa from the United States are also at high risk for infection. Schistosoma mansoni has the greatest impact on residents of disease-endemic areas who have high-grade infection and progressive hepatosplenic disease with portal hypertension and its manifestations. Most infected, short-term travelers sustain a low-level of fluke infestation with few symptoms, although serious complications can occur. We report the case of a 38-year-old American man with ectopic S. mansoni fluke migration that led to neural schistosomiasis. His symptoms prompted us to test family members who had accompanied him on a trip to Kenya 5 years earlier. The family members had been unaware of the risk for schistosomiasis. Five years after a Kenyan safari during which the index patient visited northeastern Lake Victoria and swam one afternoon, vertigo, nausea, and nystagmus developed. The results of liver function tests were normal and peripheral blood showed no eosinophilia. Biopsy of a large cerebellar lesion noted on magnetic resonance imaging (MRI) was diagnostic, yielding multiple S. mansoni ova within large eosinophilic granulomas, consistent with tumoral neuroschistosomiasis. We tested for schistosomiasis 24 of 25 family members who had accompanied him to Kenya (Figure). All of the accompanying family members, except 3 women, had gone into the water. All members were well, except an 8-year-old boy, in whom granulomatous colitis had developed after the trip. Figure Testing for Schistosoma mansoni infection among family members 5 years after trip to Kenya. ELISA, enzyme-linked immunosorbent assay. Eighteen of 25 enzyme-linked immunosorbent assays (ELISAs) were positive for S. mansoni infection, including that of samples from the index patient and the boy (Figure). ELISA was performed on 18 samples at the Centers for Disease Control and Prevention (CDC) and 7 samples at Focus Technologies. Both tests used the same CDC-produced antigen, the microsomal fraction of adult S. mansoni fluke, which has both a sensitivity and specificity for S. mansoni of 99%. Confirmatory immunoblots were performed at CDC on samples from 19 of the 25 ELISA-tested family members, with 1 discordant result, a positive ELISA and negative S. mansoni and hematobium immunoblots. Three of 7 ELISA-negative family members were the nonswimmers. Analyses of single stool specimens from 7 family members, including the index patient, and 1 rectal biopsy sample were negative for ova. Because of the high positivity rate, praziquantel was prescribed for all 26 travelers. The index patient received 20 mg/kg of praziquantel twice daily for 4 days and high-dose dexamethasone with subsequent 2-month taper; his symptoms resolved over months. An MRI 8 months after treatment demonstrated minimal residual inflammation. All other family members received 20 mg/kg of praziquantel twice in a day and tolerated it without adverse events. Ten months after treatment, the boy is growing after years of an inflammatory colitis characterized by hematochezia and growth retardation. He continues to have nonbloody diarrhea and constipation. We postulate that the mature fluke pair migrated from the mesenteric veins through Batsons vertebral-venous plexus to the cerebral veins at the cerebellar level. There, the female expelled multiple ova into the cerebellum. An ensuing vigorous granulomatous response led to posterior fossa mass effect and compression of medullary nausea centers, which resulted in the patients nausea, vertigo, and nystagmus. Ectopic ovum migration more commonly causes neuroschistosomiasis; however, in this case, multiple ova within 1 granulomatous mass suggest fluke-pair migration rather than individual ovum migration. Neuroschistosomiasis is most commonly associated with S. japonicum, which has smaller ova. In the literature, we found 16 other case-patients with intracranial tumoral S. mansoni. Eight of the patients demonstrated cerebellar involvement, which suggests a common fluke migratory pathway (3–15). Like our patient, 6 others were not native to disease-endemic regions. This unsuspected case of neural schistosomiasis illustrates the need for detailed inquiry into every freshwater exposure by persons who have traveled to schistosomiasis-endemic regions. Adult Schistosoma flukes generally survive in venules from 6 to 10 years but can survive <40 years; therefore, remote travel history is relevant. Examination of stool samples for ova has been considered the standard method of diagnosing S. mansoni and S. japonicum infection, and urine examination is used to diagnose S. haematobium. Multiple, fresh morning specimens are ideal. However, stool examination is not likely to be as sensitive as current immunologic assays for detecting low levels of infection. Moreover, in disease-nonendemic regions, operator variability may influence ova detection. Among 13 recorded cases of neurotumoral S. mansoni in which stool specimens were examined, no stool ova were found in 5 cases. In our family cohort, among the 7 ELISA-positive members who submitted stool specimens, no examinations performed at CDC demonstrated eggs (Figure). ELISA uses a highly sensitive and specific antigen for S. mansoni. Because the sensitivity is less for S. haematobium and S. japonicum, subsequent species-specific immunoblots are recommended based on travel history that suggests exposure to specific species. Thus, we recommend ELISA, immunoblot if applicable, and stool or urine examination for travelers with possible exposure in disease-endemic regions. ELISA does not have the same usefulness in persons from disease-endemic regions because positivity is also consistent with earlier infection. Stool or urine examination is diagnostic in suspected immigrant case-patients. In all cases, knowing that stool or urine examination shows ova is valuable because repeat examination at 4 to 6 weeks can be used to monitor treatment response. Because praziquantel is well tolerated and effective, empiric therapy among returning travelers after possible exposure is reasonable. However, diagnosing infection when possible and demonstrating cleared infection after therapy are more prudent approaches, particularly as praziquantel resistance emerges (16). In conclusion, pretravel counseling against freshwater exposure and posttravel screening for schistosomiasis of persons with any freshwater exposure in disease-endemic regions are warranted. As illustrated, the diagnosis of schistosomiasis in a returned traveler should prompt screening for infection in fellow travelers.

An update on Parkinson's disease: improving patient outcomes.

Neurologists are faced with many challenges in caring for patients with Parkinsons disease (PD). This chronic, long-term illness that affects at least one million people in the United States requires a coordinated healthcare partnership between the physician and the patient. The importance of early diagnosis is essential to delaying disease progression and early diagnosis and intervention may be aided by recent advances in biomarkers, genomics, and imaging. A misdiagnosis or late diagnosis will lead to deteriorating patient health. Additionally, physicians should incorporate current guidelines into their treatment strategies, and awareness of the reasoning behind these guidelines is critical for appropriate use. Physicians should be up to date on identifying the most appropriate therapies based on emerging science and disease staging, and should implement patient education into their practice. Due to limitations for currently available therapies, adjunctive therapies may lead to improved outcomes in patients with PD. The use of multiple therapies can improve myriad symptoms, more so than a monotherapy. Knowledge of these therapies is critical to achieving best outcomes in patients with PD. This webcast will discuss the current challenges with PD clinical practice, clinical features of PD, the impact of treatment, future treatments for PD and improving patient outcomes.

Posterior Reversible Encephalopathy Syndrome Presenting as Opsoclonus-Myoclonus.

Opsoclonus-myoclonus may be caused by various neurological conditions and toxic-metabolic states, but typically occurs as a parainfectious or paraneoplastic manifestation. The development of opsoclonus-myoclonus has been variably attributed to lesions in the pons or cerebellum. Herein the authors describe a case of opsoclonus-myoclonus due to posterior reversible encephalopathy syndrome in which magnetic resonance imaging revealed lesions in the region of the cerebellar dentate nuclei. Clinical and radiological resolution of the opsoclonus-myoclonus and of the posterior reversible encephalopathy syndrome followed antihypertensive therapy.

Who is helping whom? Manuscript support and transfer of value

We thank Thom and colleagues for their letter addressing human papilloma virus (HPV) in focal cortical dysplasia (FCD) and other epilepsy-associated brain pathologies. They suggest that what was previously reported as the HPV E6 oncoprotein in FCDIIB is “a cross-reaction with an as-yet unidentified neuroglial protein.” We appreciate their findings, because validation or refutation of the previous findings of HPV in FCD and glioblastoma has important public health relevance. However, several issues limit the conclusions of Thom et al, including a very small sample size, a limited description of experimental methods, incomplete experimental approaches to validate their claims, and most importantly, a failure to identify the proposed neuroglial protein. Furthermore, their report does not adequately explain the detection of the HPV viral capsid protein L1 in FCD. If the E6 oncoprotein detection is artifactual or nonpathogenic, then L1 should not be detected, because L1 and E6 are entirely nonhomologous proteins encoded by distinct genes in the HPV genome. It is puzzling that both L1 and E6 would be expressed in FCD as experimental artifact. The theory that an in utero viral infection plays a pathogenic role in brain malformations is not new and there is evidence, for example, that cytomegalovirus can cause pachygyria and smaller focal malformations. As we stated previously, the detection of E6 suggests an association between HPV and FCD but does not prove HPV pathogenicity in FCD, and further comprehensive studies are warranted to critically assess existing data sets. Until adequately powered studies are published, we stand by our original report.

Clinical utility of DaTscan™ imaging in the evaluation of patients with parkinsonism: a US perspective

ABSTRACT Introduction: Single photon emission computed tomography (SPECT) with Ioflupane I123 injection (DaTscan™) was approved by the Food and Drug Administration in 2011 for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. While brain SPECT imaging using DaTscan is a covered service under Medicare policy, there is a lack of consensus on its role in routine clinical practice in the US. Areas covered: To address this issue, an expert group of US-based movement disorders neurologists convened to discuss the clinical utility of DaTscan in movement disorders practices within the US. The group identified and discussed routine clinical scenarios where imaging with DaTscan can provide useful information that may impact management and/or clarify clinical diagnoses. This paper summarizes a consensus reached by the expert group at this meeting. Expert commentary: The major utility of DaTscan imaging is the assistance it provides in distinguishing between nigrostriatal dopaminergic degeneration and non-nigrostriatal degeneration in patients displaying equivocal signs and symptoms of parkinsonism.

Adding droxidopa to fludrocortisone or midodrine in a patient with neurogenic orthostatic hypotension and Parkinson disease

MP is a 60-year-old female who was diagnosed with Parkinson disease (PD) 6 years ago. She was started on one tablet of carbidopa/levodopa 25/100 mg three times daily (TID), in addition to carbidopa 25 mg with each dose of carbidopa/levodopa, to enhance the conversion from levodopa to dopamine in the central nervous system. Last year, her carbidopa/levodopa dosage was increased to 1.5 tablet TID, and entacapone 200 mg TID was added. Over the past 6 months, she has developed marked episodes of lightheadedness upon standing. She was evaluated by her primary care physician and diagnosed with orthostatic hypotension (OH). The doctor instructed her to use non-pharmacologic measures to help relieve her symptoms of OH, including increasing fluids, liberalizing salt intake, and wearing compression stockings. Despite these measures, she remained symptomatic so her primary care physician began treatment with fludrocortisone 0.1 mg once a day. The doctor recently increased the dose to 0.2 mg, but she still had little improvement in her symptoms of lightheadedness and dizziness upon standing. MP then saw her neurologist, and it was noted that, despite the treatment with fludrocortisone, she remained symptomatic. Office blood pressure (BP) and heart rate (HR) measurements showed that her supine BP was 178/99 mmHg with a HR of 78 beats per minute (bpm), and 3 min after standing her BP was 91/62 mmHg with an HR of 80 bpm, and she felt lightheaded. Due to her diagnosis of PD and her BP measurements, the patient was diagnosed with neurogenic OH (nOH). She remained symptomatic despite treatment with non-pharmacologic measures of liberalizing fluids, wearing compression stockings up to the abdomen, salting her food, and receiving fludrocortisone 0.2 mg/day.

The Emerging Role of Pimavanserin in the Management of Parkinson’s Disease Psychosis

A panel of experts drawn from neurology, psychiatry, geropsychiatry, geriatrics, and pharmacy representatives of 3 health plans convened in New York City on July 30, 2016, with the objective of sharing opinions, ideas, and information regarding the optimal management of Parkinsons disease psychosis (PDP). Three key points emerged from the discussion: (1) Because of the nature of Parkinsons disease and PDP, finding appropriate treatment can prove challenging; (2) emerging therapies may present an opportunity for effective disease management; and (3) moving forward, provider and patient education regarding PDP and available treatment options is essential for well-managed symptoms and better quality of life. The panel reviewed current practices and formulated recommendations on moving forward in the treatment of PDP. DISCLOSURES This project and manuscript was funded by ACADIA Pharmaceuticals and developed by Magellan Rx Management. Lopes and Farnum are employees of Magellan Rx Management. Kremens has received consulting/speaker fees from Teva Pharmaceuticals, UCB, Sunovion, Impax, Lundbeck, ACADIA, USWorldMeds, Merz, Acorda, Kyowa, Neurocrine, and GE Healthcare. Pagan reports consulting/speaker fees from Teva Nanoscience, AbbVie, Impax, ACADIA, Medtronic, USWorldMeds, Merz, and Cynapsus and research and educational grants from USWorldMeds, Teva, and Medtronic. Patel has received consultant/speaker fees from ACADIA, Allergen, and Avanir. Alva reports research support from Accera, Allergan, Axovant, Eisai, Neurotrope, Genentech, Intra Cellular, Janssen, Lundbeck, Neurim, Novartis, Otsuka, Roche, Suven, and Trans Tech and consultant/speaker fees from ACADIA, Alkermes, Allergan, Avanir, Janssen, Lundbeck, Merck, Nestle, Otsuka, Sunovion, Takeda, and Vanda. The other authors report no potential conflicts of interest, financial or otherwise.