Elizabeth A. Coon

Expanding the spectrum of neuronal pathology in multiple system atrophy

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy.

Clinical features and autonomic testing predict survival in multiple system atrophy

Multiple system atrophy is characterized by autonomic failure along with motor symptoms of parkinsonism and/or cerebellar ataxia. There are differing reports on the influence of certain clinical features, including motor subtype (multiple system atrophy-parkinsonism versus multiple system atrophy-cerebellar ataxia), age of onset, gender, and early autonomic symptoms, on the survival in patients with multiple system atrophy. We sought to evaluate overall survival and predictors of survival in a large cohort of patients with multiple system atrophy seen at a single referral centre where objective autonomic testing is routinely performed for this indication. All cases of multiple system atrophy evaluated at Mayo Clinic, Rochester and assessed with an autonomic reflex screen between January 1998 and December 2012 were retrospectively reviewed. A total of 685 patients were identified; 594 met criteria for probable multiple system atrophy, and 91 for possible multiple system atrophy. Multiple system atrophy-parkinsonism was the predominant subtype in 430 patients (63%). Average age of onset was earlier in multiple system atrophy-cerebellar ataxia (58.4 years) compared to multiple system atrophy-parkinsonism (62.3 years; P < 0.001). Median disease duration from symptom onset to death was 7.51 years (95% confidence interval 7.18-7.78) while time from diagnosis to death was 3.33 years (95% confidence interval 2.92-3.59). There was no difference in survival between motor subtypes of multiple system atrophy (P = 0.232). An initial motor symptom was most common (61%) followed by autonomic onset (28%) and combined motor and autonomic symptoms (11%). The initial onset of either motor or autonomic symptoms did not influence length of survival. However, a number of clinical and autonomic laboratory features predicted unfavourable survival in a univariate analysis. A multivariate model retained the following unfavourable predictors of survival: (i) falls within 3 years of onset (hazard ratio 2.31, P < 0.0001); (ii) bladder symptoms (hazard ratio 1.96, P < 0.0001); (iii) urinary catheterization within 3 years of symptom onset (hazard ratio 1.67, P < 0.003); (iv) orthostatic intolerance within 1 year of symptom onset (hazard ratio 1.28, P < 0.014); (v) older age of onset (hazard ratio 1.02, P = 0.001); and (vi) degree of autonomic failure as measured by a validated composite autonomic severity score (hazard ratio 1.07, P < 0.0023). We conclude that carefully selected clinical features can be used to predict survival in patients with multiple system atrophy. Autonomic testing adds an additional, independent predictor of survival, demonstrating its value not only in the diagnosis of multiple system atrophy but also as prognostic marker.

Nilotinib treatment‐associated cerebrovascular disease and stroke

also resulted from relapse and undergoing allogeneic hematopoietic cell transplantation (alloHCT). More importantly, it is obvious that patient number will decrease from beginning to the end of any therapy. Therefore, the primary question remains whether the decline rate is higher with HiDAC compared to other consolidations and the rate of decline worsens with each cycle of HiDAC. Two major prospective studies comparing HiDAC with other consolidations [4,7] showed that completion rate of the planned consolidation therapy course was similar in the HiDAC cohort compared to the other cohort. Thomas et al. noted that “despite the repetition of consolidation courses in the arm with HiDAC, toxicity was more acceptable in this arm than the arm with only one course of time-sequential chemotherapy (TSC)” (the other consolidation cohort comprised of daunorubicin, mitoxantrone, and cytarabine) [7]. Withdrawal from the study was observed in 3/ 151 (2%) in the HIDAC cohort compared to 7/155 (4.5%) in the multiagent chemotherapy (MAC) cohort [4]. One study indicated that perhaps toxicity was more common with HiDAC compared to that with MAC [6]. However, mortality rates were similar in both cohorts in the study. In addition, alloHCT was the most common reason for both cohorts not to pursue the following planned cycle. There was no evidence of accumulating toxicity of HiDAC with increased number of HiDAC cycles; the nadir of leukocyte count rates and the duration of leukopenia were the same throughout the HiDAC cycles even this study [6]. This article does not intend to discuss of HiDAC efficacy or safety compared with other consolidations. However, it shows that the published studies do not support the perception that there is accumulating hematologic or nonhematologic toxicity with increased cycle number of HiDAC. This is an interesting phenomenon and should be investigated. For at least hematologic toxicity, it might be speculated that deepening response with each HiDAC cycle may ablate suppressive effect of AML cells on normal granulocytemacrophage colony formation [10]. In addition, the number and functions of surviving neutrophils remain similar between each HiDAC cycle number, which can in part explain similar rate of infections. In conclusion, the evidence does not support the accumulative toxicity of HiDAC, and decline in patient number with each cycle is not worse than that observed with other intensive consolidation regimens. ANDRES WIERNIK WOLFGANG R. SPERR DANIEL WEISDORF PETER VALENT CELALETTIN USTUN Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota; Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria Conflict of interest: Nothing to report. *Correspondence to: Celalettin Ustun, MD, Professor of Medicine, Division of Hematology Oncology and Transplantation, Department of Medicine, University of Minnesota, 14-142 PWB, 516 Delaware Street SE, Minneapolis, MN 55455. E-mail: custun@umn.edu Received for publication 13 March 2013; Accepted 15 March 2013 Published online 22 March 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI 10.1002/ajh.23440

Predicting survival in frontotemporal dementia with motor neuron disease

Objective: To determine whether clinical and demographic features are associated with prognosis in patients with frontotemporal dementia and motor neuron disease (FTD-MND). Methods: This was a case series of FTD-MND categorized according to behavioral- or language-dominant symptoms at presentation and throughout the disease course. Demographic, clinical, imaging, and survival data were analyzed with respect to dominant FTD-MND type. Voxel-based morphometry was used to assess and compare regional patterns of atrophy in behavioral- and language-dominant FTD-MND types. Results: Of the 56 patients with FTD-MND who were identified, 31 had dominant behavioral symptoms and 25 had dominant language symptoms; 53 patients had died. A survival difference was present between types, with patients with behavioral-dominant symptoms surviving 506 days longer than patients with language-dominant symptoms (mean 1,397 vs 891 days; p = 0.002). There was also a difference in time from diagnosis to death (p = 0.02) between groups. Patients with language-dominant disease were more likely to have bulbar-onset than limb-onset motor neuron disease (MND) (p = 0.01). There was a similar pattern of frontal and temporal lobe atrophy in both types, although there was some evidence for the behavioral type to have more frontal atrophy and the language type to have more left temporal atrophy. Conclusions: In our series of patients with FTD-MND, language-dominant FTD-MND was associated with bulbar-onset MND and a shorter survival. There was also evidence that the dominant FTD-MND type is related to differences in brain atrophy patterns.

Painful Legs and Moving Toes Syndrome: A 76-Patient Case Series

OBJECTIVE To better characterize the clinical features, electrophysiologic features, and treatment outcomes of painful legs and moving toes (PLMT) syndrome. DESIGN Large case series. SETTING Neurology outpatient clinic at a tertiary referral center, 1983-2011. PATIENTS All cases of PLMT seen at our institution during an 18-year period were identified using our medical record linkage system. MAIN OUTCOME MEASURES Key demographic, clinical, imaging, and electrophysiologic features of PLMT. Treatment outcomes and long-term follow-up are also reported. RESULTS Of 76 cases identified (including 50 women [66%]), the mean age at onset was 58 years (range, 24-86 years) and at neurologic evaluation was 63 years (range, 26-88 years). Pure lower limb involvement was most common (69 patients [91%]), and 44 cases (58%) were bilateral. The most frequently diagnosed causes were peripheral neuropathy (21 cases [28%]), previous trauma (8 [11%]), and radiculopathy (7 [9%]); 32 cases (42%) were cryptogenic. Electromyography consistently showed irregular 50-millisecond to 1-second bursts of normal motor unit potential firing at 2 to 200 Hz accompanying the movements. Pain occurred first in nearly all cases and was more distressing to patients than the movements. Both components were difficult to treat, with no consistent benefit from a variety of drugs and therapeutic modalities. The syndrome persisted in most patients (83%) during the mean follow-up of 4.6 years, suggesting low likelihood of spontaneous resolution. CONCLUSIONS Painful legs and moving toes syndrome is a debilitating clinical syndrome, not because of the movements but rather because of the pain, which often is refractory to treatment. Segmental lower limb involvement is most common, and neurophysiologic findings support a pathophysiologic process localizing to a central generator at the spinal cord or brainstem level.

Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

We report a retrospective case series of four patients with genetically confirmed Huntington’s disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-50’s in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different proteinaceous inclusions coexisted in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex partly overlapped with that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.

Neuropathology of autonomic dysfunction in synucleinopathies: Autonomic Neuropathology in Synucleinopathies

The synucleinopathies—Parkinsons disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure—result from distinct patterns of abnormal α‐synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinsons disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy‐related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction.

Pure autonomic failure: Predictors of conversion to clinical CNS involvement

Objective: Based on the observation that a subset of patients originally diagnosed with pure autonomic failure (PAF) eventually develops extrapyramidal or cerebellar involvement consistent with multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB), we aimed to identify predictors of progression of PAF to more sinister synucleinopathies. Methods: In this retrospective cohort study, we reviewed patients seen at Mayo Clinic Rochester by autonomic specialists between 2001 and 2011 and during initial evaluation diagnosed with orthostatic hypotension consistent with PAF (possible PAF). In order to assess for the presence or absence of progression, we identified patients with 3 years or more of in-person follow-up (stable PAF) or documented progression to another synucleinopathy (converters). To identify predictors of conversion, we assessed odds of conversion based on clinical, autonomic, and laboratory variables. Results: Among 318 patients fulfilling criteria for possible PAF, we identified 41 with stable PAF and 37 (12%) converters. Of those who evolved, 22 developed MSA, 11 developed PD/DLB, and 4 remained indeterminate. Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss, (3) severe bladder dysfunction, (4) supine norepinephrine >100 pg/mL, and (5) subtle motor signs at first presentation. Separate variables were found to predict conversion to PD/DLB. Composite conversion scores were generated based on individual predictors. Conclusions: Over 10% of patients originally diagnosed with PAF eventually evolve to develop CNS involvement, most commonly MSA. A combination of variables allows for prediction of conversion.

Burning mouth syndrome in Parkinson’s disease: dopamine as cure or cause?

Burning mouth syndrome has been reported as being more common in Parkinson’s disease patients than the general population. While the pathophysiology is unclear, decreased dopamine levels and dopamine dysregulation are hypothesized to play a role. We report a patient with Parkinson’s disease who developed burning mouth syndrome with carbidopa/levodopa. Our patient had resolution of burning mouth symptoms when carbidopa/levodopa was replaced with a dopamine agonist. Based on our patient’s clinical course, in conjunction with earlier studies assessing the relationship between burning mouth syndrome and Parkinson’s disease, we discuss a potential role for dopamine in burning mouth syndrome in Parkinson’s disease.

Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction

The objective of this study was to characterize the degree, pattern, lesion site, and temporal evolution of sudomotor dysfunction in multiple system atrophy (MSA) and to evaluate differences by parkinsonian (MSA‐parkinsonism) and cerebellar (MSA‐cerebellar) subtypes.