Arm Swing while Walking and Running: A New Clinical Feature to Separate Parkinson's Disease from Functional Parkinsonism.

BACKGROUND: Functional parkinsonism is an important differential diagnosis of Parkinson's disease (PD). Based on anecdotal experience, we hypothesized that arm swing while walking and running could differentiate these two conditions, but this assumption has not been previously explored systematically. OBJECTIVES: To examine differences in arm swing while walking and running between patients with PD and functional parkinsonism. METHODS: We analyzed blinded video assessments of arm swing and other gait parameters in patients with asymmetrical PD (n = 81) and functional parkinsonism (n = 8) while walking and running. The groups were matched for age, sex and disease duration. RESULTS: In contrast to those with PD, patients with functional parkinsonism (i) were more likely to have a marked asymmetry in arm swing while walking (5/8 vs. 25/81; P = 0.06), (ii) were less likely to improve arm swing while running with full effort (3/8 vs. 72/81; P < 0.001) and (iii) demonstrated normal passive arm swing even when asymmetry of arm swing was marked during running/walking (6/6 vs. 9/33; P = 0.002). CONCLUSIONS: Assessment of arm swing while walking and running and passive arm swing could be important differentiating clinical features between functional parkinsonism and PD.

Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype-phenotype associations in HSP with a focus on movement disorders. METHODS: We performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder. RESULTS: The HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5). CONCLUSION: This systematic IPD-level meta-analysis provides the largest data on genotype-phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.

α-Synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders.

Lewy body disorders (LBD), characterized by the deposition of misfolded α-synuclein (α-Syn), are clinically heterogeneous. Although the distribution of α-Syn correlates with the predominant clinical features, the burden of pathology does not fully explain the observed variability in clinical presentation and rate of disease progression. We hypothesized that this heterogeneity might reflect α-Syn molecular diversity, between both patients and different brain regions. Using an ultra-sensitive assay, we evaluated α-Syn seeding in 8 brain regions from 30 LBD patients with different clinical phenotypes and disease durations. Comparing seeding across the clinical phenotypes revealed that hippocampal α-Syn from patients with a cognitive-predominant phenotype had significantly higher seeding capacity than that derived from patients with a motor-predominant phenotype, whose nigral-derived α-Syn in turn had higher seeding capacity than that from cognitive-predominant patients. Interestingly, α-Syn from patients with rapid disease progression (< 3 years to development of advanced disease) had the highest nigral seeding capacity of all the patients included. To validate these findings and explore factors underlying seeding heterogeneity, we performed in vitro toxicity assays, and detailed neuropathological and biochemical examinations. Furthermore, and for the first time, we performed a proteomic-wide profiling of the substantia nigra from 5 high seeder and 5 low seeder patients. The proteomic data suggests a significant disruption in mitochondrial function and lipid metabolism in high seeder cases compared to the low seeders. These observations suggest that distinct molecular populations of α-Syn may contribute to heterogeneity in phenotypes and progression rates in LBD and imply that effective therapeutic strategies might need to be directed at an ensemble of differently misfolded α-Syn species, with the relative contribution of their differing impacts accounting for heterogeneity in the neurodegenerative process.

ß-Blocker-Induced Tremor.

BACKGROUND: Although the ß-blocker propranolol is considered one of the most effective tremor treatments and other ß-blockers are often prescribed to patients with tremor, those with partial ß-agonist activity on ß-adrenoreceptors can theoretically induce or exacerbate tremor. Here we report 2 patients with tremor induced or worsened by such ß-blockers. CASES: Case 1 is a 38-year-old man with worsening of tremor in both upper extremities after the introduction of pindolol as an adjunct treatment for severe depression. The tremor improved 1 month after discontinuing this medication. Case 2 is a 77-year-old woman with new bilateral hand tremor after receiving labetalol for the management of hypertension during a hospital admission. Tremor markedly attenuated after eliminating labetalol. CONCLUSION: ß-Blockers with partial agonist activity can induce or exacerbate tremor.

Movement Disorders and Renal Diseases.

Movement disorders often emerge from the interplay of complex pathophysiological processes involving the kidneys and the nervous system. Tremor, myoclonus, ataxia, chorea, and parkinsonism can occur in the context of renal dysfunction (azotemia and electrolyte abnormalities) or they can be part of complications of its management (dialysis and renal transplantation). On the other hand, myoglobinuria from rhabdomyolysis in status dystonicus and certain drugs used in the management of movement disorders can cause nephrotoxicity. Distinct from these well-recognized associations, it is important to appreciate that there are several inherited and acquired disorders in which movement abnormalities do not occur as a consequence of renal dysfunction or vice versa but are manifestations of common pathophysiological processes affecting the nervous system and the kidneys. These disorders are the emphasis of this review. Increasing awareness of these conditions among neurologists may help them to identify renal involvement earlier, take timely intervention by anticipating complications and focus on therapies targeting common mechanisms in addition to symptomatic management of movement disorders. Recognition of renal impairment in a patient with complex neurological presentation may narrow down the differentials and aid in reaching a definite diagnosis.

Non-Dopaminergic Treatments for Motor Control in Parkinson's Disease: An Update.

Glutamatergic, noradrenergic, serotonergic, and cholinergic systems play a critical role in the basal ganglia circuitry. Targeting these non-dopaminergic receptors remains a focus of ongoing research to improve Parkinson's disease (PD) motor symptoms, without the potential side effects of dopamine replacement therapy. This review updates advancements in non-dopaminergic treatments for motor control in PD since 2013. To date, no non-dopaminergic selective drug has shown significant long-term efficacy as monotherapy in PD. The largest area of development in non-dopaminergic targets has been for motor complications of dopamine replacement therapy (motor fluctuations and dyskinesia). For treatment of motor fluctuations, safinamide, zonisamide, and istradefylline are currently approved, and novel glutamatergic and serotonergic drugs are in development. Long-acting formulations of amantadine are approved for treating dyskinesia. Several non-dopaminergic drugs have failed to show anti-dyskinetic efficacy, while some are still in development. Non-dopaminergic targets are also being pursued to treat specific motor symptoms of PD. For example, CX-8998 (a calcium channel modulator) is being evaluated for PD tremor and rivastigmine may improve gait dysfunction in PD. Drug repurposing continues to be a key strategy for non-dopaminergic targets in PD, but the field needs to increase discovery and availability of such drugs.

Clinical and radiological spectrum of intracranial tuberculosis: A hospital based study in Northeast India.

Central nervous system tuberculosis (TB) is the most severe extra pulmonary TB having a high mortality and morbidity. OBJECTIVE: To study the various clinical, biochemical, and radiological spectrum of intracranial TB. MATERIALS AND METHOD: Ninety-three patients were enrolled in this prospective study after ethical clearance and consent from August 2013 to May 2015. The entire clinical course with complications and predictors of mortality were assessed. RESULTS: 36 females (38.7%) and 57 males (61.3%) were included whose mean age of presentation was 32.3±17.05 years. Alcohol was the most common risk factor seen in 19.4%. Headache (90.3%) was the most common symptom. Co-infection with human immunodeficiency virus, cryptococcal, and toxoplasmosis were seen in 11, 3, and 2 patients, respectively. Cerebrospinal fluid analysis showed acid-fast bacilli in 1 patient; polymerase chain reaction for TB and BACTEC was positive in one and three patients, respectively. Neuroimaging showed basal exudates (21.7%), tuberculoma (28.6%), brain edema (27%), hydrocephalus (32.9%), infarct (21%), and abscess (2.9%). Complications were noted such as brain edema (24.7%), vasculitis (26.9%), hydrocephalus (17.2%), hyponatremia (11.8%), drug-induced hepatitis (4.3%), and drug rash in 5 patients (5.4%). A total of 25 patients (26.9%) died and 38 patients (40.9%) developed neurological sequelae like hemiparesis, paraparesis, visual loss, and hearing loss. Logistic regression showed that a Glasgow scale of <10, British Medical Research Council stage 3, and vasculitis were associated with poor outcome. CONCLUSION: Lack of sensitive diagnostic method and criteria makes central nervous system TB a challenge where early diagnosis and prompt management is required.

Etiological profile of noncompressive myelopathies in a tertiary care hospital of Northeast India.

BACKGROUND: The discovery of antibodies against aquaporin-4 and evolving concepts of noncompressive myelopathies in the 21st century have made a major impact on the etiological profile of these diseases, with few cases turning out to be idiopathic. OBJECTIVE: To find causes of noncompressive myelopathy in a tertiary care hospital of Northeast India. MATERIALS AND METHODS: An observational study was carried out in the Neurology Department of Gauhati Medical College, Guwahati, from September 2013 to February 2016. Patients of noncompressive myelopathies who underwent magnetic resonance imaging (MRI) of the spine were segregated into two categories: acute-to-subacute myelopathy (ASM) and chronic myelopathy (CM). In addition to routine blood tests, chest X-ray, urinalysis, and visual evoked potentials, investigations included MRI of the brain, cerebrospinal fluid analysis, and immunological, infectious, and metabolic profile based on the pattern of involvement. RESULTS: The study had 151 patients (96 ASM and 55 CM) with a median age of 35 years and male: female ratio 1.4:1. The causes of ASM were neuromyelitis optica spectrum disorder (23), multiple sclerosis (MS) (8), systemic lupus erythematosus (1), Hashimoto's disease (1), postinfectious acute disseminated encephalomyelitis (6), postinfectious myelitis (8), infections (9), spinal cord infarct (5), and electrocution (1). The causes of CM were MS (1), probable or possible sarcoidosis (7), mixed connective tissue disease (1), Hashimoto's disease (2), infections (9), Vitamin B12 deficiency (4), folate deficiency (2), hepatic myelopathy (2), radiation (11), and paraneoplastic (1). No etiology could be found in 48 (31.8%) patients (34 ASM and 14 CM). In 21/96 (21.9%) patients of ASM, acute transverse myelitis was idiopathic based on current diagnostic criteria. CONCLUSION: Underlying etiology (demyelinating, autoimmune, infectious, vascular, metabolic disorder, or physical agent) was found in 68% patients of noncompressive myelopathy.

Relapsing Anti-NMDAR Encephalitis after a gap of eight years in a girl from North-East India.

It has been just 7 years since the discovery of anti-NMDAR encephalitis as distinct immune-mediated encephalitis and we have such cases being reported from our country. Herein, we describe a case of a 13-year-old girl who had relapsing encephalitis consisting of multiple types of difficult-to-control seizures, abnormal behavior, language disintegration, memory loss and abnormal movements eight years after the first clinical attack. In 2005, when she was 5 yearsold, anti-NMDAR encephalitis was not yet discovered and she was provisionally diagnosed as a case of viral encephalitis. During her second attack in 2013, antibodies against NMDAR were demonstrated by immunofluoresence in serum (1:10). This is the first report from our country of a case of relapsing anti-NMDAR encephalitis of such a long duration, successfully treated by immunotherapy.