Toxin Induced Parkinsonism and Hospitalization Related Adverse Outcome Mitigation for Parkinson's Disease: A Comprehensive Review.

Patients with Parkinson's disease admitted to the hospital have unique presentations. This unique subset of patients requires a multidisciplinary approach with a knowledge-based care team that can demonstrate awareness of complications specific to Parkinson's disease to reduce critical care admissions, morbidity, and mortality. Early recognition of toxic exposures, medication withdrawals, or medication-induced symptoms can reduce morbidity and mortality. This review can assist in the critical assessment of new or exacerbating Parkinson's disease symptoms.

Impact of botulinum toxin injection into the masticatory muscles on mandibular bone: A systematic review.

BACKGROUND: Botulinum toxin type A (BoNTA) injection into the masticatory muscles has been widely used to treat a number of painful and nonpainful conditions; however, no systematic reviews have been performed on the long-term effect to the mandibular bone. OBJECTIVE: Our systematic review aimed to evaluate the impact of botulinum toxin injection into the masticatory muscles on mandibular bone based. METHODS: PubMed, Embase, Ovid, CINAHL and Web of Science were searched for human studies assessing mandibular bone after injection of BoNTA using computed tomography (CT) and cone beam CT (CBCT). RESULTS: Seven studies were eligible for review; five reported significant bony changes to one or more areas of the mandible. Most frequently affected were the condylar head, coronoid process and ramus. The most frequent changes were decreased bone volume, cortical thickness and cortical and trabecular density. CONCLUSIONS: This is the first systematic review to examine an association between BoNTA injection into the masticatory muscles and mandibular bone quality. Data were analysed from a limited number of studies with a small sample size, and the quality of the included studies was very low. While the majority of available evidence suggests BoNTA injection results in bony change, further study is required to confirm a dose-dependence effect and the impact of gender and age. High-quality trials should utilise a combination of software analysis and radiologist review, with longer-term follow-up to monitor for persistence of bony effect and clinical significance.

Improving access to care for patients with migraine in a remote Pacific population.

OBJECTIVE: To evaluate the efficacy of increasing access to care for patients with migraines in a rural setting. Outcomes include decreased resource utilization, decreased hospitalizations, polypharmacy reduction, and decreased disability in a remote Pacific population. METHODS: Data were collected on all patients presenting to a single neurologist in a deployed military setting for migraines. Access to care was supplemented through health fairs, radio shows, telemedicine, and education of primary care providers. RESULTS: Over the course of 1 year, 300 providers were educated through public health fairs and telemedicine counseling. This strategy helped reduce consults by 50% and decrease clinic wait times from 2 months to 7 days. Two hundred twenty-one patients with chronic migraine or episodic migraine were seen in the neurology clinic over the course of 1 year. Of these patients, polypharmacy reduction was achieved in 71% of patients with chronic migraines and in 44% of patients with episodic migraines. Over the course of 1 year, only 13% of patients with chronic migraines and 11% of patients with episodic migraines were treated in an acute care setting. Less than 2% of patients had limitations in their work duties because of migraines. CONCLUSION: Increased access to care provided benefits in reduction of specialist overutilization, reduction in hospitalizations, and reduction in disability. Patients with chronic migraine did not have increased use of medical resources or decreased productivity in this cohort.

Toxin-Induced Parkinsonism.

Toxins identified as causing parkinsonism and being related to overall idiopathic Parkinson disease risk range from heavy metals to pesticides to contaminants in synthetic heroin. Several described in this article exhibit significant oxidative stress on neurons of the central nervous system and have a particular predilection toward damage of dopaminergic neurons. Although many of these toxins have well-established connections with Parkinson disease risk, a few continue to be studied with data still being produced. The parkinsonisms caused by these agents have variable responses to dopaminergic therapies. This article discusses manganese, mercury, MPTP, organochlorines, organophosphates, paraquat, rotenone, and Agent Orange.

Lost productivity associated with headache and depression: a quality improvement project identifying a patient population at risk.

OBJECTIVE: This quality improvement project was implemented in order to highlight the association between headache, mTBI and depression on lost productivity and resource utilization. BACKGROUND: Mood disorders, environment and traumatic brain injury are common in patients with headache, and have been shown to influence clinical course, treatment response and outcome. Although widely recognized, the association of these factors on clinical outcomes, resource utilization and productivity is not well understood. METHODS: All patients presenting to a military referral center for migraines are assessed for presence of traumatic brain injury, Headache Impact Score (HIT-6) and Patient Depression Questionnaire (PHQ-9). Based on screening, patients are offered referral to mental health and a multidisciplinary headache education course. RESULTS: 237 patients were seen for headache or migraine. 180 patients had severely disabling headaches. These patients accounted for 146 emergency room visits over the course of one year. Of headache patients, 65% met criteria for depression and 15% of patients had severe depression. Only 37% of these patients carried a formal diagnosis of depression and 38% had been seen by mental health. Lost productivity and duty limitations were significantly associated with severity of depression. In service members screening positively for mild, moderate or severe depression, duty restrictions had been placed on 8.3%, 32.5% and 53.8%, respectively. Only 3.8% of patients who did not screen for depression had similar duty limitations. A history of mTBI strongly correlated with comorbid depression. Lost productivity and duty limitations were not impacted by other headache characteristics or HIT-6 scores. CONCLUSIONS: This quality improvement project identified a practice gap for treatment of comorbid depression in patients presenting to Neurology for headache. Depression strongly correlated with productivity loss, highlighting a possible target for the economic burden of headache.

Lifestyle modifications as therapy for medication refractory post-traumatic headache (PTHA) in the military population of Okinawa.

OBJECTIVE: Our aim was 1) to reduce disability, as characterized by headache frequency, duration and severity in patients with post-traumatic headache (PTHA), 2) to reduce the number of medical boards and work limitations in patients with post traumatic headache, and 3) to reduce use of medical resources and clinic visits related to headache or migraine. BACKGROUND: Modifiable risk factors for PTHA include stressful life event, sleep disturbances, and medication overuse. Cognitive-behavioral strategies, biofeedback, and relaxation therapy may have an important role in treatment and preventing progression to chronic post-traumatic headache (CPTHA). There is limited literature and a known practice gap for implementation of these techniques. DESIGN/METHODS: An IRB approved project focused on patients who were seen for PTHA and CPTHA. 1) Intervention consisted of lifestyle teaching, cognitive-behavioral therapy and biofeedback, supplemented by decreasing polypharmacy. 2) Patients were followed for 2 years and a retrospective review was conducted for 2 years prior to presentation. 3) Outcome measures included reduction in migraine intensity or frequency, improved quality of life, duty status, and decreased utilization of clinic visits. RESULTS: Over the course of one year, 221 patients were treated for migraines in the Naval Okinawa Neurology Clinic. Of these, 22 active duty service members and 3 Dependents suffered a mild TBI prior to onset. After intervention, there was a 36% decrease in PTHA frequency, 56% decrease in headache severity and 60% of patients had improved quality of life as compared to the 2 years prior to intervention. Twenty-four percent had reduction in polypharmacy. Appointment frequency for migraine decreased from an average of 6.8 to 2.6 per year. CONCLUSIONS: An implemented program geared towards reducing polypharmacy was shown to improve safety, quality of life and reduce hospitalizations from the burden of migraines. Our systematic approach resulted in quality of life improvements and decreased use of medical resources. TRIAL REGISTRATION: Authors received the approval of NAVMED West, Okinawa Naval Hospital Institutional Review Board on January 13th, 2016. QI.2016.0021.

Distribution and Quantity of Sites of John Cunningham Virus Persistence in Immunologically Healthy Patients: Correlation With John Cunningham Virus Antibody and Urine John Cunningham Virus DNA.

Importance: Although seroepidemiological studies indicate that greater than 50% of the population has been infected with John Cunningham virus (JCV), the sites of JCV persistence remain incompletely characterized. Objective: To determine sites of JCV persistence in immunologically healthy individuals. Design, Setting, and Participants: Tissue specimens from multiple sites including brain, renal, and nonrenal tissues were obtained at autopsy performed in the Department of Pathology at the University of Kentucky from 12 immunologically healthy patients between February 9, 2011, and November 27, 2012. Quantitative polymerase chain reaction was performed on the tissue specimens and urine. Serum JCV antibody status was determined by enzyme-linked immunosorbent assay. Main Outcomes and Measures: The detection and quantification of JCV from the tissues by quantitative polymerase chain reaction illuminated sites of viral persistence. These results were correlated with JCV antibody levels. Results: Autopsies were performed on 12 individuals, 10 men and 2 women, ranging in age from 25 to 75 years (mean, 55.3 years). Seven of 12 individuals were JCV antibody seropositive based on absorbance units. Serostatus was associated with amounts of JCV DNA in urine and its tissue distribution. John Cunningham virus DNA was found in 75% of genitourinary tissue samples from donors (18 of 24) with high JCV antibody levels, 13.3% of donors with low levels i(4 of 30), and 0% of seronegative persons (0 of 32). In nongenitourinary tissues, JCV DNA was detected in 45.1% of tissue samples of donors (32 of 71) with high JCV, 2.2% of donors with low JCV serostatus (2 of 93), and 0% of seronegative persons (0 of 43). Genitourinary tissues had higher copy numbers than other sites. John Cunningham virus DNA was detected in urine of seronegative individuals in a research-grade assay. Conclusions and Relevance: Persistent (latent or actively replicating) JCV infection mostly predominates in genitourinary tissues but distributes in other tissues at low copy number. The distribution and copy numbers of the virus appear to correlate with urinary JCV shedding and serostatus.

Randomized, Blinded Pilot Testing of Nonconventional Stimulation Patterns and Shapes in Parkinson's Disease and Essential Tremor: Evidence for Further Evaluating Narrow and Biphasic Pulses.

OBJECTIVES: Evidence suggests that nonconventional programming may improve deep brain stimulation (DBS) therapy for movement disorders. The primary objective was to assess feasibility of testing the tolerability of several nonconventional settings in Parkinson's disease (PD) and essential tremor (ET) subjects in a single office visit. Secondary objectives were to explore for potential efficacy signals and to assess the energy demand on the implantable pulse-generators (IPGs). MATERIALS AND METHODS: A custom firmware (FW) application was developed and acutely uploaded to the IPGs of eight PD and three ET subjects, allowing delivery of several nonconventional DBS settings, including narrow pulse widths, square biphasic pulses, and irregular pulse patterns. Standard clinical rating scales and several objective measures were used to compare motor outcomes with sham, clinically-optimal and nonconventional settings. Blinded and randomized testing was conducted in a traditional office setting. RESULTS: Overall, the nonconventional settings were well tolerated. Under these conditions it was also possible to detect clinically-relevant differences in DBS responses using clinical rating scales but not objective measures. Compared to the clinically-optimal settings, some nonconventional settings appeared to offer similar benefit (e.g., narrow pulse widths) and others lesser benefit. Moreover, the results suggest that square biphasic pulses may deliver greater benefit. No unexpected IPG efficiency disadvantages were associated with delivering nonconventional settings. CONCLUSIONS: It is feasible to acutely screen nonconventional DBS settings using controlled study designs in traditional office settings. Simple IPG FW upgrades may provide more DBS programming options for optimizing therapy. Potential advantages of narrow and biphasic pulses deserve follow up.

Deep Brain Stimulation in a Case of Mitochondrial Disease.

BACKGROUND: DBS has proven to be an effective therapy for Parkinson's disease, essential tremor, and primary dystonia. Mixed results have been reported in case series for other hyperkinetic disorders, and sparse data are available regarding secondary movement disorders. We report on the clinical effects of bilateral globus pallidus internus (GPi) DBS, a progressive mitochondrial cytopathy. METHODS: A single patient with myoclonus and dystonia syndrome secondary to a mitochondrial cytopathy with history of perinatal hypoxia was identified from our University of Florida DBS database. Demographics, clinical, surgical, and DBS data were documented. RESULTS: At 6 months post-DBS, we observed a 32% (361 to 527) improvement on quality of life (36-item Medical Outcome Study Short-Form Health Survey; SF-36). Objective clinical scales revealed a 33% (143 to 96) improvement in the Unified Myoclonus Rating Scale (UMRS) total score. The UMRS action myoclonus subsection revealed a 29% (69 to 46) improvement. No significant changes were observed in the Burke-Fahn-Mardsen Dystonia Rating Scale (BFMDRS). After 1-year follow-up, a worsening of 59% (527 to 215) was observed in the SF-36 scale, of 19% (28.5 to 35) in the BFMDRS, and of 23% (96 to 124) in the UMRS. However, the frequency and intensity of action myoclonus scores remained lower when compared to baseline scores. CONCLUSIONS: Although we observed a loss of benefit in the long term for most quality-of-life and clinical outcomes, the DBS effects on action myoclonus seemed to remain stable. Longer follow-up studies are necessary to confirm our short-term and unblinded findings.

Incidence and mortality trends of aspiration pneumonia in Parkinson's disease in the United States, 1979-2010.

INTRODUCTION: Careful examination of long-term analyses and trends is essential in understanding the medico-economic burden of this common complication. We sought to describe the long-term (32-year) trends of incidence and mortality in PD patients hospitalized with aspiration pneumonia (AsPNA). METHODS: Incidence and mortality of AsPNA in hospitalized PD versus non-PD patients was assessed by logistic regression analysis applied to a national database between the years 1979 and 2010. Covariates such as age-decennium, gender, year AsPNA occurred, and the interactions with PD diagnosis were investigated. Rate of AsPNA and mortality over the 32-years was trended and compared. RESULTS: AsPNA occurred in 3.6% of PD patients and 1.0% of non-PD patients. The average mortality for PD patients was less (17% vs. 22%). Long-term (32-year) trends revealed a nearly 10-fold increase in incidence of AsPNA in PD (0.4% in 1979, 4.9% in 2010), decreasing mortality overtime, higher likelihood in males, and increasing average age of AsPNA patients (steeper increase in PD). All p-values<0.05. In regression analysis, each successive year had a slight increase in odds of AsPNA (OR 1.03 in PD, OR1.06 in non-PD). CONCLUSIONS: Trends over 32 years revealed a 10-fold increase in AsPNA among PD and non-PD patients, and an associated decrease in mortality. Our data suggest that PD patients are living longer, have slightly more AsPNA, but a lower mortality than was seen in past decades. Further research should investigate the causes of AsPNA in PD, and also potential interventions to decrease its occurrence.

Discriminating features of gait performance in progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) is the most common form of atypical Parkinsonism; however it is underdiagnosed and often misdiagnosed as Parkinson's disease (PD). METHODS: We investigated gait initiation (GI) and gait performance in a total of 36 participants (12 PSP, 12 PD and 12 healthy age- and gender-matched controls) to gain further insight into specific motor deficits that characterize dynamic postural control and gait in PSP. Anticipatory postural adjustments (APAs), quantified by center of pressure (COP) displacement and speed prior to an initial heel off, and the maximum distance (COPCOM) between COP and center of mass (COM) during all three GI phases were calculated to evaluate dynamic postural control. Steady-state gait performance was also evaluated and compared across the groups. RESULTS: APAs in PSP were significantly altered such that the posterior COP shift is profoundly diminished when compared to PD (p < 0.05). Moreover, proper velocity control during GI in PSP was affected, particularly in the mediolateral direction, when compared to PD (p < 0.05). The diminished COPCOM distance is further indicative of more severe dynamic postural instability in PSP than in PD (p < 0.05). Significant differences in spatiotemporal parameters, inter-step variability, and asymmetry during gait in PSP, in comparison with PD were also identified (all p's < 0.05). CONCLUSION: The present study reveals that the compensatory GI strategy in PSP is distinct from PD and paradoxically induces lateral instability. Further, gait performance in PSP is slower and more variable which could be the consequence of lateral instability and fear of falling.

Person-Centered Care in the Home Setting for Parkinson's Disease: Operation House Call Quality of Care Pilot Study.

Objective. (1) To evaluate the feasibility of implementing and evaluating a home visit program for persons with Parkinson's disease (PD) in a rural setting. (2) To have movement disorders fellows coordinate and manage health care delivery. Background. The University of Florida, Center for Movement Disorders and Neurorestoration established Operation House Call to serve patients with PD who could not otherwise afford to travel to an expert center or to pay for medical care. PD is known to lead to significant disability, frequent hospitalization, early nursing home placement, and morbidity. Methods. This was designed as a quality improvement project. Movement disorders fellows travelled to the home(s) of underserved PD patients and coordinated their clinical care. The diagnosis of Parkinson's disease was confirmed using standardized criteria, and the Unified Parkinson's Disease Rating Scale was performed and best treatment practices were delivered. Results. All seven patients have been followed up longitudinally every 3 to 6 months in the home setting, and they remain functional and independent. None of the patients have been hospitalized for PD related complications. Each patient has a new updatable electronic medical record. All Operation House Call cases are presented during video rounds for the interdisciplinary PD team to make recommendations for care (neurology, neurosurgery, neuropsychology, psychiatry, physical therapy, occupational therapy, speech therapy, and social work). One Operation House Call patient has successfully received deep brain stimulation (DBS). Conclusion. This program is a pilot program that has demonstrated that it is possible to provide person-centered care in the home setting for PD patients. This program could provide a proof of concept for the construction of a larger visiting physician or nurse program.

Weight loss and impact on quality of life in Parkinson's disease.

INTRODUCTION: Weight loss is common in Parkinson's Disease (PD) and sometimes may precede the diagnosis. Weight loss is associated with multiple factors but its impact on health-related quality of life (HRQL) in PD remains unknown. We sought to investigate the factors associated with weight change and to quantify its effect on HRQL. METHODS: The National Parkinson Foundation Quality Improvement Initiative (NPF-QII) data was used to analyze PD patients longitudinally between two visits, separated by 12 ± 6 months. Multiple linear regression analyses were used to assess the associations between baseline covariates and body weight change per month, and to evaluate whether, and to what degree, Parkinson's Disease Questionnaire (PDQ-39) scores were affected. RESULTS: A higher Hoehn & Yahr stage, higher number of comorbidities, older age, lower MOCA estimate, and higher rate of levodopa usage were observed in patients who lost weight. Multivariate regression analysis indicated that age and levodopa usage were significantly associated with weight loss. Furthermore, monthly body weight loss was significantly associated with HRQL decline in PD patients. Loss of 1 lb (0.45 kg) per month was associated with a decline in QOL: an increase of 0.5% in PDQ-39 Summary Index score (p=0.004), and 1.1% and 1.5% increases in the mobility and ADL dimensions, respectively. CONCLUSION: Weight loss in PD is common and seems to correlate with worsened HRQL. Awareness of factors associated with weight loss and its relation to HRQL may help practitioners improve patient management and expectations.

Rehabilitation outcomes after combined acute disseminated encephalomyelitis and Guillain-Barré syndrome in a child: a case report.

A 5-year old female presented with acute tetraparesis and areflexia. Initial imaging and cerebrospinal fluid analysis were suggestive of acute disseminated encephalomyelitis (ADEM). Minimal clinical response with intravenous steroids prompted further work up. Limited nerve conduction studies suggested possible acute motor-sensory axonal neuropathy, a rare variant of Guillain-Barré syndrome (GBS). Repeat imaging was compatible with polyradiculopathy indicating concomitance of ADEM and GBS. The patient suffered severe motor deficits and neuropathic pain. Slow but significant functional recovery was noted after intensive inpatient rehabilitation followed by continued rehabilitation via home health services.

Impulsive and compulsive behaviors in Parkinson Study Group (PSG) centers performing deep brain stimulation surgery.

BACKGROUND: Impulse control disorders (ICDs), dopamine dysregulation syndrome (DDS), and dopamine agonist withdrawal syndrome (DAWS) have been reported commonly in Parkinson's disease (PD) populations. The treatment approaches may be widely variable and there is not much information on these syndromes in the setting of deep brain stimulation (DBS). OBJECTIVE: To evaluate (1) ICDs, DAWS and DDS pre- and post DBS in PD and (2) to investigate pre-DBS treatment strategies regarding these behaviors among Parkinson Study Group (PSG) centers. METHODS: Forty-eight PSG centers were surveyed on ICDs, DAWS and DDS, as well as on potential relationships to DBS and treatment approaches. RESULTS: Sixty-seven percent of PSG centers reported that they served a population of over 500 PD patients per year, and 94% of centers performed DBS surgery. Most centers (92%) reported screening for ICDs, DAWS and DDS. Of the centers screening for these symptoms, 13% reported always employing a formal battery of pre-operative tests, 46% of sites inconsistently used a formal battery, while 23% of sites reported never using a formal battery to screen for these symptoms. The estimated numbers of centers observing ICDs, DAWS and DDS pre-operatively in individuals with PD were 71%, 69%, and 69%, respectively. PSG DBS centers observing at least one case of a new de novo occurrence of an ICD, DAWS or DDS after DBS surgery were 67%, 65% and 65%, respectively. CONCLUSIONS: The results suggest that addiction-like syndromes and withdrawal syndromes are prevalent in expert PSG centers performing DBS. Most centers reported screening for these issues without the use of a formal battery, and there were a large number of centers reporting ICDs, DAWS and DDS post-DBS. A single treatment strategy did not emerge.

Effects of dopaminergic therapy on locomotor adaptation and adaptive learning in persons with Parkinson's disease.

Persons with Parkinson's disease (PD) are characterized by multifactorial gait deficits, though the factors which influence the abilities of persons with PD to adapt and store new gait patterns are unclear. The purpose of this study was to investigate the effects of dopaminergic therapy on the abilities of persons with PD to adapt and store gait parameters during split-belt treadmill (SBT) walking. Ten participants with idiopathic PD who were being treated with stable doses of orally-administered dopaminergic therapy participated. All participants performed two randomized testing sessions on separate days: once while optimally-medicated (ON meds) and once after 12-h withdrawal from dopaminergic medication (OFF meds). During each session, locomotor adaptation was investigated as the participants walked on a SBT for 10 min while the belts moved at a 2:1 speed ratio. We assessed locomotor adaptive learning by quantifying: (1) aftereffects during de-adaptation (once the belts returned to tied speeds immediately following SBT walking) and (2) savings during re-adaptation (as the participants repeated the same SBT walking task after washout of aftereffects following the initial SBT task). The withholding of dopaminergic medication diminished step length aftereffects significantly during de-adaptation. However, both locomotor adaptation and savings were unaffected by levodopa. These findings suggest that dopaminergic pathways influence aftereffect storage but do not influence locomotor adaptation or savings within a single session of SBT walking. It appears important that persons with PD should be optimally-medicated if walking on the SBT as gait rehabilitation.

An eight-year clinic experience with clozapine use in a Parkinson's disease clinic setting.

BACKGROUND: To examine our eight year clinic-based experience in a Parkinson's disease expert clinical care center using clozapine as a treatment for refractory psychosis in Parkinson's disease (PD). METHODS: The study was a retrospective chart review which covered eight years of clozapine registry use. Statistical T-tests, chi-square, correlations and regression analysis were used to analyze treatment response for potential associations of age, disease duration, and Hoehn & Yahr (H&Y) score, and degree of response to clozapine therapy. RESULTS: There were 36 participants included in the analysis (32 PD, 4 parkinsonism-plus). The characteristics included 30.6% female, age 45-87 years (mean 68.3±10.15), disease duration of 17-240 months (mean 108.14±51.13) and H&Y score of 2 to 4 (mean 2.51±0.51). The overall retention rate on clozapine was 41% and the most common reasons for discontinuation were frequent blood testing (28%), nursing home (NH) placement (11%) and leucopenia (8%). Responses to clozapine across the cohort were: complete (33%), partial (33%), absent (16%), and unknown (16%). Age (r = -0.36, p<0.01) and H&Y score (r = -0.41, p<0.01) were shown to be related to response to clozapine therapy, but disease duration was not an associated factor (r = 0.21, p>0.05). CONCLUSIONS: This single-center experience highlights the challenges associated with clozapine therapy in PD psychosis. Frequent blood testing remains a significant barrier for clozapine, even in patients with therapeutic benefit. Surprisingly, all patients admitted to a NH discontinued clozapine due to logistical issues of administration and monitoring within that setting. Consideration of the barriers to clozapine therapy will be important to its use and to its continued success in an outpatient setting.

Substantia nigra depigmentation and exposure to encephalitis lethargica.

OBJECTIVE: Parkinsonism has occasionally been reported as a consequence of infectious diseases. The present study examines the clinical and pathological correlates of parkinsonism across birth cohorts in relation to critical exposure to the encephalitis lethargica epidemic in the early 1900s. METHODS: The study population consisted of 678 participants in the Nun Study, of whom 432 died and came to autopsy. Qualitative indices of substantia nigra (SN) depigmentation were verified in a subset of 40 randomly selected subjects using quantitative stereological techniques. SN depigmentation, detected neuropathologically, was correlated with clinical parameters of Parkinson disease, age, and birth cohort. RESULTS: SN depigmentation was detected in 57 (13.2%) of the cohort. Although qualitative SN depigmentation correlated modestly with age (p = 0.02), it correlated best with birth cohort (p = 0.009) for women born in the years 1895-1899. Quantitative measures of SN depigmentation were increased in this birth cohort compared to age matched subjects from flanking birth cohorts 1890-1894 and 1900-1904 (p < 0.001). SN depigmentation correlated with speed of 6- and 50-foot walk (p < 0.0001), up and go test (p < 0.0001), and hand coordination (p < 0.0001). INTERPRETATION: Subjects in the birth cohort 1895-1899 would have been in their late teens and 20s at the onset and during the peak of the encephalitis lethargica epidemic. These were precisely the age ranges of persons who were most often affected by the illness. These data suggest the possibility that the coexistence of parkinsonism and SN depigmentation in this birth cohort may have resulted from the yet undetermined infectious agent responsible for encephalitis lethargica.