Recipient Reaction and Composition of Autologous Sural Nerve Tissue Grafts into the Human Brain.

Parkinson's disease (PD) is a severe neurological disease for which there is no effective treatment or cure, and therefore it remains an unmet need in medicine. We present data from four participants who received autologous transplantation of small pieces of sural nerve tissue into either the basal forebrain containing the nucleus basalis of Meynert (NBM) or the midbrain substantia nigra (SN). The grafts did not exhibit significant cell death or severe host-tissue reaction up to 55 months post-grafting and contained peripheral cells. Dopaminergic neurites showed active growth in the graft area and into the graft in the SN graft, and cholinergic neurites were abundant near the graft in the NBM. These results provide a histological basis for changes in clinical features after autologous peripheral nerve tissue grafting into the NBM or SN in PD.

Direct delivery of an investigational cell therapy in patients with Parkinson's disease: an interim analysis of feasibility and safety of an open-label study using DBS-Plus clinical trial design.

Objective: To evaluate the interim feasibility, safety and clinical measures data of direct delivery of regenerating peripheral nerve tissue (PNT) to the substantia nigra (SN) in participants with Parkinson's disease (PD). Methods: Eighteen (13 men/5 women) participants were unilaterally implanted with PNT to the SN, contralateral to the most affected side during the same surgery they were receiving deep brain stimulation (DBS) surgery. Autologous PNT was collected from the sural nerve. Participants were followed for safety and clinical outcomes for 2 years (including off-state Unified Parkinson's Disease Rating Scale (UPDRS) Part III assessments) with study visits every 6 months. Results: All 18 participants scheduled to receive PNT implantation received targeted delivery to the SN in addition to their DBS. All subjects were discharged the following day except for two: post-op day 2; post-op day 3. The most common study-related adverse events were hypoaesthesia and hyperaesthesias to the lateral aspect of the foot and ankle of the biopsied nerve (6 of 18 participants experienced). Clinical measures did not identify any hastening of PD measures providing evidence of safety and tolerability. Off-state UPDRS Part III mean difference scores were reduced at 12 months compared with baseline (difference=-8.1, 95% CI -2.4 to -13.9 points, p=0.005). No complications involving dyskinesias were observed. Conclusions: Targeting the SN for direct delivery of PNT was feasible with no serious adverse events related to the study intervention. Interim clinical outcomes show promising results meriting continued examination of this investigational approach. Trial registration number: NCT02369003.

Use of anti-TNF-α therapy in Crohn's disease is associated with increased incidence of multiple sclerosis.

OBJECTIVE: We investigated if anti-tumor necrosis factor-α (anti-TNF-α) drugs used in the treatment of inflammatory bowel disease (IBD) alter the incidence of MS and if so, to understand the magnitude of such an effect. METHODS: This is a retrospective cohort study of data from Truven Health Market Scan administrative claims database. The patients included in the study had to be ≥ 18 years of age. The presence of IBD was based on at least 2 claims of International Classification of Diseases (ICD-9 or 10) diagnosis codes. The IBD diagnosis index date had to precede the MS diagnosis index date for inclusion in the study. The diagnosis of multiple sclerosis (MS) was defined as having at least 2 claims for the disease (ICD 9, 340 and ICD 10 codes, G35) and at least one prescription claim for any of the drugs that were defined as MS therapy. RESULTS: Patients with IBD had 1.32 times the risk of MS incidence compared to healthy controls (adjusted incidence rate ratio (IRR): 1.32; 95% CI: 1.03 - 1.71; p = .0312). Patients with IBD exposed to anti-TNF-α therapies had a 43% increase in the incidence of MS compared to those with IBD without exposure (adjusted incidence rate: 1.43; 95% CI: .062 - 3.32; p = .3989). Among CD patients treated anti-TNF-α medications an increase in the incidence of MS, compared to CD patients not exposed to such medications was observed (IRR = 2.62; 95% CI: 1.00 to 6.83; p = 0.049), statistically significant. After adjusting for age/gender, patients with CD using anti-TNF-α agents had an increase of incidence in MS (adjusted IRR: 2.24; 95% CI: 0.85 - 5.94; p = .1035) but it was not statistically significant. CONCLUSIONS: Use of anti-TNF-α drugs in CD was associated with a statistically significant increase in the incidence of MS but this effect was lost when controlled for age/gender.

Gait and Balance Changes with Investigational Peripheral Nerve Cell Therapy during Deep Brain Stimulation in People with Parkinson's Disease.

BACKGROUND: The efficacy of deep brain stimulation (DBS) and dopaminergic therapy is known to decrease over time. Hence, a new investigational approach combines implanting autologous injury-activated peripheral nerve grafts (APNG) at the time of bilateral DBS surgery to the globus pallidus interna. OBJECTIVES: In a study where APNG was unilaterally implanted into the substantia nigra, we explored the effects on clinical gait and balance assessments over two years in 14 individuals with Parkinson's disease. METHODS: Computerized gait and balance evaluations were performed without medication, and stimulation was in the off state for at least 12 h to best assess the role of APNG implantation alone. We hypothesized that APNG might improve gait and balance deficits associated with PD. RESULTS: While people with a degenerative movement disorder typically worsen with time, none of the gait parameters significantly changed across visits in this 24 month study. The postural stability item in the UPDRS did not worsen from baseline to the 24-month follow-up. However, we measured gait and balance improvements in the two most affected individuals, who had moderate PD. In these two individuals, we observed an increase in gait velocity and step length that persisted over 6 and 24 months. CONCLUSIONS: Participants did not show worsening of gait and balance performance in the off therapy state two years after surgery, while the two most severely affected participants showed improved performance. Further studies may better address the long-term maintanenace of these results.

Anti-MOG and Anti-AQP4 positive neuromyelitis optica spectrum disorder in a patient with myasthenia gravis.

Aquaporin 4 antibody (anti-AQP4) positive neuromyelitis optica spectrum disorder (NMOSD) is known to occur in the setting of myasthenia gravis (MG). However, comorbid MG with myelin oligodendrocyte glycoprotein antibody (anti-MOG) positive NMOSD has not been reported. We present a case of anti-MOG and anti-AQP4 positive NMOSD in a patient with long-standing MG. The patient presented with acute right-sided weakness with MRI demonstrating extensive spinal cord edema extending from T2 to the medulla with associated contrast enhancement. To our knowledge, this is the first reported case of anti-MOG and anti-AQP4 positive NMOSD in a patient with known MG.

RNA Sequencing of Human Peripheral Nerve in Response to Injury: Distinctive Analysis of the Nerve Repair Pathways.

The development of regenerative therapies for central nervous system diseases can likely benefit from an understanding of the peripheral nervous system repair process, particularly in identifying potential gene pathways involved in human nerve repair. This study employed RNA sequencing (RNA-seq) technology to analyze the whole transcriptome profile of the human peripheral nerve in response to an injury. The distal sural nerve was exposed, completely transected, and a 1 to 2 cm section of nerve fascicles was collected for RNA-seq from six participants with Parkinson's disease, ranging in age between 53 and 70 yr. Two weeks after the initial injury, another section of the nerve fascicles of the distal and pre-degenerated stump of the nerve was dissected and processed for RNA-seq studies. An initial analysis between the pre-lesion status and the postinjury gene expression revealed 3,641 genes that were significantly differentially expressed. In addition, the results support a clear transdifferentiation process that occurred by the end of the 2-wk postinjury. Gene ontology (GO) and hierarchical clustering were used to identify the major signaling pathways affected by the injury. In contrast to previous nonclinical studies, important changes were observed in molecular pathways related to antiapoptotic signaling, neurotrophic factor processes, cell motility, and immune cell chemotactic signaling. The results of our current study provide new insights regarding the essential interactions of different molecular pathways that drive neuronal repair and axonal regeneration in humans.

Can a diagnosis of multiple sclerosis be made without ruling out neuromyelitis optica spectrum disorder ?

BACKGROUND: The symptoms of multiple sclerosis (MS) can overlap with neuromyelitis optica spectrum disorder (NMOSD). Although testing is available for aquaporin 4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies, screening for NMOSD is recommended but not mandatory to establish a diagnosis of MS. METHODS AND RESULTS: We queried 319,994 individuals who filed claims for MS and NMOSD in a Truven Health Analytics (THA) database and had at least one year of uninterrupted health insurance coverage. Of this cohort, 2001 (0.62%) were diagnosed as having NMOSD after an initial diagnosis of MS, based on ICD 9/10 codes. Since THA only offers claims-based data, we initiated an individual patient-based data search at our medical center to screen for potential misdiagnoses. We identified 4/54 (7.4%) NMOSD cases that were initially diagnosed as having MS. CONCLUSIONS: The results from our small study have significant implications--symptoms, clinical presentation or classic radiological findings perhaps cannot reliably separate MS from NMOSD. If our study findings can be replicated, guidelines to diagnose MS ought to recommend that NMOSD be excluded first despite typical clinical and radiological findings pointing to MS.

New generation VMAT2 inhibitors induced parkinsonism.

•Drug induced parkinsonism caused by valbenazine and deutetrabenazine.•Possible side effects of VMAT-2 inhibitors.•Valbenazine and deutetrabenazine can unmask underlying Parkinson's Disease.

Bilateral Facial Spasm Following Guillain-Barré Syndrome.

Background: We report a patient who developed lower facial muscle spasm at rest and bilateral facial synkinesis several months after treatment of Guillain-Barré syndrome (GBS); this finding, to our knowledge, is hitherto unreported. Phenomenology Shown: Bilateral synkinesis, facial muscles spasm at rest, bilateral postparalytic facial syndrome. Educational Value: Aberrant regeneration of nerve fibers post GBS, resulting in facial muscles spasm at rest, bilateral synkinesis.

Unusual case of recurrent SMART (stroke-like migraine attacks after radiation therapy) syndrome.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare delayed complication of cerebral radiation therapy. A 53-year-old female initially presented with headache, confusion and left homonymous hemianopia. Her medical history was notable for cerebellar hemangioblastoma, which was treated with radiation in 1987. Her initial brain MRI (magnetic resonance imaging) revealed cortical enhancement in the right temporo-parieto-occipital region. She improved spontaneously in 2 weeks and follow-up scan at 4 weeks revealed no residual enhancement or encephalomalacia. She presented 6 weeks later with aphasia. Her MRI brain revealed similar contrast-enhancing cortical lesion but on the left side. Repeat CSF studies was again negative other than elevated protein. She was treated conservatively and recovered completely within a week. Before diagnosing SMART syndrome, it is important to rule out tumor recurrence, encephalitis, posterior reversible encephalopathy syndrome (PRES) and stroke. Typically the condition is self-limiting, and gradually resolves.