Pravin Khemani

Automated Gait and Balance Parameters Diagnose and Correlate with Severity in Parkinson Disease

OBJECTIVE To assess the suitability of instrumented gait and balance measures for diagnosis and estimation of disease severity in PD. METHODS Each subject performed iTUG (instrumented Timed-Up-and-Go) and iSway (instrumented Sway) using the APDM(®) Mobility Lab. MDS-UPDRS parts II and III, a postural instability and gait disorder (PIGD) score, the mobility subscale of the PDQ-39, and Hoehn & Yahr stage were measured in the PD cohort. Two sets of gait and balance variables were defined by high correlation with diagnosis or disease severity and were evaluated using multiple linear and logistic regressions, ROC analyses, and t-tests. RESULTS 135 PD subjects and 66 age-matched controls were evaluated in this prospective cohort study. We found that both iTUG and iSway variables differentiated PD subjects from controls (area under the ROC curve was 0.82 and 0.75 respectively) and correlated with all PD severity measures (R(2) ranging from 0.18 to 0.61). Objective exam-based scores correlated more strongly with iTUG than iSway. The chosen set of iTUG variables was abnormal in very mild disease. Age and gender influenced gait and balance parameters and were therefore controlled in all analyses. INTERPRETATION Our study identified sets of iTUG and iSway variables which correlate with PD severity measures and differentiate PD subjects from controls. These gait and balance measures could potentially serve as markers of PD progression and are under evaluation for this purpose in the ongoing NIH Parkinson Disease Biomarker Program.

The spectrum of autoimmune encephalopathies

Despite being a potentially reversible neurological condition, no clear guidelines for diagnosis or management of autoimmune encephalitis exist. In this study we analyzed clinical presentation, laboratory and imaging characteristics, and outcome of autoimmune encephalitis from three teaching hospitals. Non-paraneoplastic autoimmune encephalitis associated with antibodies against membrane antigens was the most common syndrome, especially in the pediatric population. Clinical outcome was better for patients with shorter latency from symptom onset to diagnosis and initiation of immunomodulation. Patients with underlying malignancy were less likely to respond well to immunomodulatory therapy. The clinical spectrum of autoimmune encephalitis is fairly broad, but prompt recognition and treatment often leads to excellent outcome.

Deep brain stimulation of the subthalamic nucleus: taking the ouch out of Parkinson disease

Parkinsondisease (PD) is knowntoaffectmultipleneurotransmitter systems, resulting in both motor and nonmotor symptoms. Pain is an underrecognized but important nonmotor symptom of PD that may be verydisablingandisknownto impair quality of life.1 While significantprogresshasbeenmadeinamelioratingmotorsymptomsusing pharmacological, rehabilitative, and surgical treatments, thetreatmentofpain inthiscontexthasnotreceivedsufficientattention.Aliteraturereview2notedareportedprevalence ofpain inPDof40%to85%,yetonlyabouthalf ofpatientswith PDwhofeltpaintookanalgesics.ClassifyingPD-relatedpaininto its subtypes3 is important for rational treatment, and themost common subtypes of pain in PD are musculoskeletal and dystonic, with central neuropathic pain being the least common.2 Toaddresspainsuccessfully inPD,anunderstandingof itspathogenesis is important, yet this has remained elusive, in part because its causes areprotean. Just as certainmotor symptomsof PD aremore responsive to dopaminergic drugs and deep brain stimulation (DBS), somepainsubtypesmayrespondbetter than others to pharmacological and surgical intervention. Dysfunction of both dopaminergic and nondopaminergic basal ganglia pathwaysare likelytobe involvedinPD-relatedpain,whichmay explainwhysome typesofpain are responsive to levodopaand others are not.4 Deep brain stimulation of the subthalamic nucleus (STN) isnowanestablished treatmentofdisablingmotor symptoms in advanced PD, and it is therefore important to understand its effect on pain associated with PD. Previous reports5,6 on the effects of STNDBSonpain inPDshowthat the levelsofmusculoskeletal anddystonicpaindecreasedwhenassessed1yearafter surgery,but, toourknowledge, there isnoexisting information on the status of chronic pain. In this issue of JAMA Neurology, Jung and colleagues7 investigate the long-termeffect of STNDBSonpain in24patients withPDwhowereobservedfor8yearsafterundergoingtheprocedure for alleviating disabling motor symptoms. The beneficial effectsofSTNDBS in this cohort 3monthsafter surgeryand 24monthsafter surgeryhavebeenpreviouslypublished.8,9The subtypes of painwere classified according to Ford.3 The severity and body distribution of pain were compared between presurgical andpostsurgical states. Jungandcolleagues7notedsignificant improvement at 8 years in all pain types present preoperatively, regardlessofwhether thepreoperativepainwas responsive to levodopa or not.However, newpain, not present before surgery, developed in 75% of patients during prolonged follow-up. Musculoskeletal pain accounted for the majority of newpain cases. Although themean severity of painwas less at 8 years than at baseline,more patients experienced pain at the end of the observation period than preoperatively. Because previous studies on pain following STN DBS for PD are of short duration, the durability of the procedure’s effect on pain is not well established. The chief strength of the work by Jung and colleagues7 is the long follow-up period, which suggests that, althoughDBSmay relievepain for a time, this is not a durable effect owing to the onset of new, primarilymusculoskeletal pain.A recent report5wasconcordantwith the study by Jung and colleagues7 in showing the benefit of DBS on dystonic and musculoskeletal pain but was discordant in showingnoeffect ofDBSoncentral and radicular pain. Methodological differences, the subjective classification of pain, andamuchshorter observationperiod couldaccount for these discrepant findings. The study by Jung and colleagues7 has several limitations that the authors acknowledge, including a small cohort without a control group thatwas treatedmedically, the lack of correlation of pain scores with motor Unified Parkinson’s Disease Rating Scale scores (especially rigidity, which can potentially impact musculoskeletal pain), the lack of measures of disability or effect of pain on quality of life, and the lackofmoodandcognitiveassessments that can influencepain perception. In addition, an analysis of the effect of levodopa onpreoperative pain vs the effect of DBS onpainwas not performed. This would have been of interest in light of a previous report10 suggesting that the effects of DBS on pain can be predicted by measuring the effects of levodopa on pain. Despiteits limitations,thestudybyJungandcolleagues7providesanovelperspectiveon thedurabilityof thepain-relieving properties of STN DBS in PD. The authors direct our attention tothefactthatmusculoskeletalpainmayemergeyearsafterDBS, warranting individualized treatment. The next step is to pursueadeeperunderstandingof themechanismofpain inPD.Previous work11 with small numbers of participants has demonstrated altered pain processing in participants with PD who experienced pain comparedwith those who did not, such that STN DBS raises pain thresholds selectively in those who experiencepain.Althoughthere isagrowingconsensusthatSTNDBS decreases the level of pain in people with PD, the literature is mixed on the subtypes of pain that are responsive to DBS, and the study by Jung and colleagues7 shows that new pain arising years after the procedure is common. This underscores the importance of performing future trialswith larger cohorts, longer observational periods, and standard methods to enable effective interpretation of outcomes. For now,we have learned that STNDBS does not take the ouch out of PD in the long run. Related article page 504 Opinion

Psychosis in Parkinson Disease: A Review of Etiology, Phenomenology, and Management.

Parkinson disease psychosis (PDP) is a common phenomenon in Parkinson disease (PD) patients treated with dopaminergic drugs, and is associated with high morbidity and mortality. It also correlates with depression and dementia, and can contribute to considerable caregiver stress and burnout. While symptoms can be relieved by decreasing doses or number of anti-PD medications, this may lead to an unacceptable worsening of motor function. When general medical or psychiatric conditions have been ruled out, and decreasing dopaminergic agents is not effective in treating psychosis, therapies include atypical antipsychotics, primarily clozapine and quetiapine. Of these, clozapine is effective but is associated with a poor side-effect profile and the necessity for frequent blood draws. Clinicians prefer quetiapine for its theoretically better safety profile, although there is no evidence for efficacy in treating psychosis. All atypical antipsychotics are associated with increased mortality in this patient population. Cholinesterase inhibitors can ameliorate psychosis symptoms. The serotonin 5-HT2A receptor inverse agonist pimavanserin was recently approved by the US FDA for the treatment of PDP and may prove to be a more targeted therapy without the downsides of atypical antipsychotics.

Charcot Marie Tooth disease type 4J with complex central nervous system features

We describe a family with Charcot Marie Tooth disease type 4J presenting with features of Charcot Marie Tooth disease plus parkinsonism and aphemia. Genetic testing found two variants in the FIG4 gene: c.122T>C (p.I41T) – the most common Charcot Marie Tooth disease type 4J variant – and c.1949‐10T>G (intronic). Proband fibroblasts showed absent FIG4 protein on western blot, and skipping of exon 18 by RT‐PCR. As most patients with Charcot Marie Tooth disease type 4J do not have central nervous system deficits, we postulate the intronic variant and I41T mutation together are causing loss of FIG4 protein and subsequently the central nervous system findings in our family.

Gradually Progressive Spastic Ataxia in a Young Man: Steadily Unsteady.

A 26-year-old right-handed man presented with progressive gait imbalance over 6 years. His examination was consistent with cerebellar and upper motor neuronal dysfunction. He had no significant family history. Most of the serum and cerebrospinal fluid studies were unremarkable. Neuroimaging was remarkable for mild cerebellar and noticeable thoracic spinal cord atrophy. The initial differential diagnosis for the patient’s presentation was broad, but because of certain clinical characteristics, it was later focused on hereditary ataxias. Detailed analysis of the clinical features in the history, neurologic examination, and neuroimaging studies led to the diagnosis.

Developing a Deep Brain Stimulation Neuromodulation Network for Parkinson Disease, Essential Tremor, and Dystonia: Report of a Quality Improvement Project.

Objective To develop a process to improve patient outcomes from deep brain stimulation (DBS) surgery for Parkinson disease (PD), essential tremor (ET), and dystonia. Methods We employed standard quality improvement methodology using the Plan-Do-Study-Act process to improve patient selection, surgical DBS lead implantation, postoperative programming, and ongoing assessment of patient outcomes. Results The result of this quality improvement process was the development of a neuromodulation network. The key aspect of this program is rigorous patient assessment of both motor and non-motor outcomes tracked longitudinally using a REDCap database. We describe how this information is used to identify problems and to initiate Plan-Do-Study-Act cycles to address them. Preliminary outcomes data is presented for the cohort of PD and ET patients who have received surgery since the creation of the neuromodulation network. Conclusions Careful outcomes tracking is essential to ensure quality in a complex therapeutic endeavor like DBS surgery for movement disorders. The REDCap database system is well suited to store outcomes data for the purpose of ongoing quality assurance monitoring.

Cystic Lesions as a Rare Complication of Deep Brain Stimulation

DBS is a typically well‐tolerated operation for treatment of Parkinsons disease, dystonia, and essential tremor (ET). Complications related to the surgical procedure and implanted hardware may occur. More commonly reported complications include hemorrhage, seizure, confusion, and infection. In this article, we report on a rare, but important, complication of DBS surgery, a brain cyst formation at the tip of the implanted ventralis intermedius nucleus (VIM) DBS lead in 2 patients who underwent the procedure at 2 different centers. The indication for surgery was debilitating ET, and in both cases, there was development of a delayed‐onset neurological deficit associated with an internal capsule/thalamic cystic lesion formation located at the tip of the DBS lead. Case 1 presented within a few months post‐DBS, whereas case 2 had a 10‐mo delay to onset of symptoms. No clinical and radiological signs of infection were observed and both DBS systems were explanted with uneventful recovery.

The Inherited Ataxias

Abstract Of the syndromes constituting the inherited ataxias, some show autosomal dominant or recessive inheritance, and others are caused by mitochondrial mutations and thus show maternal inheritance. Significant progress has been made in defining the molecular basis of these syndromes, so that a genotype classification now supersedes previous ones based on clinical features alone.

Metastatic “Burned Out” Seminoma Causing Neurological Paraneoplastic Syndrome—Not Quite “Burned Out”

A 44-year-old man presented with cerebellar ataxia and limbic encephalitis and was ultimately diagnosed with metastatic germ cell neoplasm resulting from a “burned out” primary testicular tumor. The patient had progressive ataxia, leading to a thorough investigation for infectious, autoimmune, metabolic, and malignant causes of acquired cerebellar ataxia that revealed no significant findings. Testicular sonography demonstrated a possible right testicular lesion that was not confirmed on radical inguinal orchiectomy. F18-FDG positron emission tomography/computerized tomography scan revealed a solitary retroperitoneal lesion, concerning for metastatic disease but not amenable to percutaneous biopsy. A robotic retroperitoneal lymph node dissection was performed and pathology revealed a CD117-positive metastatic seminoma leading to appropriate germ cell tumor-directed chemotherapy. After completing chemotherapy and during 1 year of follow-up, there has been a gradual improvement of the patient’s neurological manifestations.