Progressive Apathy Research Articles

Extreme Delta Brush Electroencephalography Pattern in Anti-yo Encephalitis: A Case Report

Autoimmune encephalitis is complex and gradually being recognized. Anti-N-methyl-D-aspartate Receptor (Anti-NMDAR) encephalitis was the most well-known and its unique electroencephalography (EEG) pattern is extreme delta brush (EDB). Anti-Yo encephalitits is far less than common anti-NMDAR encephalitis (anti-NMDARE). A 78-year-old male presented with progressive apathy, hypotension, unsteady gait, and depressed consciousness. EEG revealed an EDB pattern while the serum test was positive for anti-Yo antibodies. The patient then received 10 rounds of plasma exchange, and his blood pressure stability improved. Consequently, urine cytology and abdominal computed tomography revealed atypical cells and linear enhancement in the bladder dome, respectively. However, instead of further pathological confirmation and treatment, the patient’s family requested hospice care. As a result, the patient died of desaturation 7 days later after the withdrawal of ventilatory support. First recognized in 2012, EDB is believed to be specific to NMDARE. However, to date, EDB has not been well described, and no description is available regarding its reactivity. To our knowledge, this is the first case of EDB with anti-Yo encephalitis. Similar to the cases of EDB with anti-NMDARE, our patient did not have satisfied prognosis despite no further investigation and treatment of the possible underlying malignancy. As the prevalence and underlying mechanism of this EEG pattern are unclear, further studies are warranted to identify the potentially similar mechanisms and correlation between anti-NMDAR and anti-Yo encephalitis.

Glial Fibrillary Acidic Protein (GFAP) Antibody-Associated Astrocytopathy in Systemic Sarcoidosis

Objective To report two cases of glial fibrillary acidic protein (GFAP) antibody-associated meningoencephalitis in patients with biopsy-proven systemic sarcoidosis. Background GFAP astrocytopathy is an autoimmune neurologic disease first defined in 2016. To our knowledge, no association with systemic sarcoidosis has been previously reported. Design/Methods Case Series Results Patient 1 is a 47-year-old woman with pre-existing pulmonary sarcoidosis treated with steroids and methotrexate with remission 6 years prior. She subsequently developed new-onset epilepsy, progressive ataxia and vertical diplopia. GFAP antibodies were positive in the cerebrospinal fluid (CSF) by cell-based assay (CBA). Body PET scan showed diffuse FDG avidity in her lungs, spleen, and lymph nodes, suggesting simultaneous reactivation of her systemic sarcoidosis. She was treated with steroids followed by infliximab with resolution of her symptoms. Patient 2 is a 58-year-old man with known pulmonary sarcoidosis, who was off immunosuppression at the time of his presentation but had received steroids 17 years prior. He presented with progressive apathy, memory disturbance, dysarthria, and gait instability. MRI revealed widespread T2 hyperintensities. GFAP antibodies were positive in CSF on CBA and confirmed by tissue-based immunofluorescence assay. He received steroids with initial response but relapsed after steroid discontinuation. He improved after restarting steroids and was subsequently transitioned to infliximab with sustained neurologic recovery. Conclusions Sarcoidosis is a poorly understood multi-system disorder that is presumably an immune-mediated response to yet unidentified antigen(s). It is known to co-exist with other autoimmune diseases, with autoimmune thyroiditis being most common. GFAP astrocytopathy is also poorly understood. GFAP is found intracellularly and similar to other antibody-mediated diseases against intracellular epitopes, the antibodies are believed to be a biomarker of underlying autoimmunity but not directly pathogenic. We report these cases to highlight a potential association between production of intrathecal GFAP antibodies and systemic sarcoidosis, which may provide insights into the pathogenesis of these two diseases.

Teaching Video NeuroImage: Generalized Reflex Myoclonus in Autoimmune Hepatitis-Primary Biliary Cholangitis Overlap Syndrome.

A 25-year-old woman presented with progressive apathy and disorientation, followed by acute-onset confusion that progressed to stupor. Physical examination revealed generalized reflex myoclonus to both tactile (Video 1, part 1) and visual stimuli (part 2). Hepatic and autoimmune workup was positive for transaminitis, hyperammonemia, and antimitochondrial and anti-smooth muscle antibodies (Table). The rest of her laboratory test results including chemistries were within normal limits. MRI of the brain was likewise unremarkable. EEG showed generalized slowing. She was diagnosed with autoimmune hepatitis-primary biliary cholangitis overlap syndrome1 with hepatic encephalopathy. She was treated with steroids with full resolution of her myoclonus (Video 1, part 3). Hepatic encephalopathy is usually associated with negative myoclonus (asterixis) rather than reflex myoclonus. Little is known about the mechanism of reflex myoclonus, although small studies suggest cortical and subcortical subtypes reflect the origin of electrical signals leading to the myoclonic jerks.2

Alzheimer’s Disease and Tau Self-Assembly: In the Search of the Missing Link

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease characterized by progressive cognitive impairment, apathy, and neuropsychiatric disorders. Two main pathological hallmarks have been described: neurofibrillary tangles, consisting of tau oligomers (hyperphosphorylated tau) and Aβ plaques. The influence of protein kinases and phosphatases on the hyperphosphorylation of tau is already known. Hyperphosphorylated tau undergoes conformational changes that promote its self-assembly. However, the process involving these mechanisms is yet to be elucidated. In vitro recombinant tau can be aggregated by the action of polyanions, such as heparin, arachidonic acid, and more recently, the action of polyphosphates. However, how that process occurs in vivo is yet to be understood. In this review, searching the most accurate and updated literature on the matter, we focus on the precise molecular events linking tau modifications, its misfolding and the initiation of its pathological self-assembly. Among these, we can identify challenges regarding tau phosphorylation, the link between tau heteroarylations and the onset of its self-assembly, as well as the possible metabolic pathways involving natural polyphosphates, that may play a role in tau self-assembly.

De novo PSEN1 mutation (Pro436Gln) in a very early onset posterior variant of Alzheimer's disease is associated with pyramidal signs.

Alzheimer's disease (AD) is a common cause of dementia even in cases with very early onset, and implication of monogenic mutations in the PSEN1, PSEN2, and APP genes must be considered. Strong family history is the rule in autosomal dominant AD associated with mutations in these genes but, in rare cases, de novo mutations can occur. Case report of a sporadic AD case with onset in his twenties carrying the Pro436Gln mutation (exon 12, TM-9 region) in PSEN1. Comparison with a previously reported familial case carrying the same mutation. A 32 years old male consulted for a 10 years-long mild but slowly progressive learning difficulties, apathy and anxiety. There was no family history of neurologic diseases and both parents were cognitively preserved in their early 70s. The previous two years he had developed progressive visual disturbances including impaired reading, recognizing numbers, letters and faces and, more recently, he had experienced troubles with manual praxias. There were no specific complaints regarding episodic memory. Neuropsychological assessment showed severe visual agnosia and mild impairments in memory, speech, and executive functions. Neurologic examination showed brief distal myoclonus in upper limbs, markedly enhanced reflexes in lower limbs, as well as mild spasticiy. Blood tests, EEG, spinal MRI, and SSEP were normal. Brain MRI and FDG-PET revealed severe parieto-occipital atrophy/hypoperfusion (fig. 1-4). AD CSF biomarkers showed decrease in Ab1-42 and 1-42/1-40 ratio, increased pTau and normal total tau. Amyloid-PET was positive, identifying a high burden of amyloid plaques in posterior cortex. The pathogenic PSEN1 mutation was found in the patient but was absent in his parents. It is remarkable that the phenotype of the previously reported case with this mutation was almost identical as regards onset in the late twenties and associated pyramidalism. PSEN1 mutations should be considered in patients with sporadic very early onset dementia, as de novo mutations may occur. AD CSF biomarkers offer valuable diagnostic information in such cases. The specific mutation has a very strong impact in the clinical phenotype. Further, this case is another example that PSEN1 mutations affecting proline residues have the earliest age at onset.

New Frontiers in the Prevention, Diagnosis, and Treatment of Alzheimer's Disease.

One of the major puzzles in medical research and public health systems worldwide is Alzheimer's disease (AD), reaching nowadays a prevalence near 50 million people. This is a multifactorial brain disorder characterized by progressive cognitive impairment, apathy, and mood and neuropsychiatric disorders. The main risk of AD is aging; a normal biological process associated with a continuum dynamic involving a gradual loss of people's physical capacities, but with a sound experienced view of life. Studies suggest that AD is a break from normal aging with changes in the powerful functional capacities of neurons as well as in the mechanisms of neuronal protection. In this context, an important path has been opened toward AD prevention considering that there are elements of nutrition, daily exercise, avoidance of toxic substances and drugs, an active social life, meditation, and control of stress, to achieve healthy aging. Here, we analyze the involvement of such factors and how to control environmental risk factors for a better quality of life. Prevention as well as innovative screening programs for early detection of the disease using reliable biomarkers are becoming critical to control the disease. In addition, the failure of traditional pharmacological treatments and search for new drugs has stimulated the emergence of nutraceutical compounds in the context of a "multitarget" therapy, as well as mindfulness approaches shown to be effective in the aging, and applied to the control of AD. An integrated approach involving all these preventive factors combined with novel pharmacological approaches should pave the way for the future control of the disease.

Rangelia vitalii infection in a dog from São Paulo city, Brazil: case report

Canine rangeliosis is an extravascular hemolytic disease caused by the protozoan Rangelia vitalii, which is transmitted by ticks of the species Amblyomma aureolatum. Te most common clinical signs are apathy, hyperthermia and spontaneous bleeding. Anemia and thrombocytopenia are the most common hematological fndings. Tis work reports a clinical case of canine Rangeliosis treated at a private veterinary hospital, in São Paulo city in 2017. A dog was treated at a veterinary hospital in the north of São Paulo, with progressive weight loss, apathy and tail injury. Anemia and thrombocytopenia were observed on the hemogram. Rangelia vitalii DNA was detected in animal blood by real-time PCR (qPCR). In addition to the supportive treatment, doxycycline and subcutaneous imidocarb applications were used. Te sample collected afer treatment with the antibiotic continued to present protozoal DNA. Te disease should be considered as a diferential diagnosis and there is a great need for further studies about the therapy used.

Chronic renal failure in equine due to ascending pyelonephritis predisposed by cauda equina syndrome: case report

ABSTRACT This report describes the case of a mare, of the Campeiro breed, used as an embryo donor, which had recurrent cystitis and urinary incontinence crisis. Clinical signs evolved to progressive weight loss, anorexia, apathy, and isolation from the group. Physical examination showed tail hypotonia, perineal hypalgesia, rectal and bladder sagging compatible with signs related to cauda equina syndrome. Complementary laboratory and sonographic assessment, and necropsy confirmed the diagnosis of chronic renal failure (CRF), which was attributed to the ascending pyelonephritis. The examination of urine culture showed growth of bacteria of the genus Streptococcus sp. This is a rare case in the equine species where the lower motor neuron dysfunction led the development of infectious process in the urinary tract, progressing to renal chronic condition incompatible with life.

HG-77RADIATION-INDUCED HIGH GRADE GLIOMA FOLLOWING I-125 BRACHYTHERAPY IN A PEDIATRIC PATIENT

HG-77. RADIATION-INDUCED HIGH GRADE GLIOMA FOLLOWING I-125 BRACHYTHERAPY IN A PEDIATRIC PATIENT Daniela Garcez, Eduardo Netto, and Duarte Salgado; Instituto Portugues de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal INTRODUCTION: Brachytherapy has been used in brain tumors since 1960. Only a few studies have been published about late occurence of second malignancies due to brachytherapy for brain tumors. Therefore, this procedureappears to be an attractive alternative in multimodality cancer management in selected pediatric cases. CASE PRESENTATION: We report the case of a 33 years old female patient diagnosed with an anaplastic ependymoma grade III (right frontal lobe) when she was 8 years old. After a total resection she underwent craniospinal radiotherapy (36Gy) with a focal boost (54Gy). A local relapse was identified three years later and pathological diagnosis, after total resection, was ependymoblastoma. She received I-125 brachytherapy for 3 months followed by 8 cycles of CCNU, cisplatin and vincristine. She remained in total remission for almost 20 years. In 2015 she was admitted due to progressive apathy. An MRI scan showed a large contrast enhancing tumor (8x7cm) in the right frontal lobewith mass effect and midline shift. After subtotal resection the pathological diagnosis was anaplastic oligodendroglioma. CONCLUSION: Despite the obvious advantages that I-125 brachytherapy presents, the use in the pediatric population remains controversial.Radiation-induced tumors area serious issue andareusuallyagressiveand sometimes fatal. The enhanced risk of associating standard external beam radiotherapy with brachytherapy should be carefully considered in the pediatric population. Neuro-Oncology 18:iii48–iii77, 2016. doi:10.1093/neuonc/now073.73 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Clinical and pathological aspects of chronic Senecio spp. poisoning in sheep

This paper describes an outbreak of chronic Senecio spp. poisoning in grazing sheep in Rio Grande do Sul, Brazil, causing the death of 10 out of 860 adult sheep. Eight sick ewes were euthanized and necropsied. Cattle from this farm were also affected. Clinical signs included progressive weight loss, apathy and photosensitization. Four out of seven tested sheep had increased gamma-glutamyl transferase serum activity and two of them presented serum elevation of alkaline phosphatase. At necropsy, three out of eight ewes presented slightly irregular toughened livers with multifocal nodules, two out of eight ewes had a whitish liver with thickened fibrotic Glisson's capsule partially adhered to the diaphragm, and three out of eight ewes had smooth and grossly normal livers. Necropsy findings attributed to liver failure included hydropericardium (7/8), ascites (5/8), icterus (2/8), hydrothorax (1/8), and edema of mesentery (1/8). The main hepatic histological findings that allowed the establishment of the diagnosis were megalocytosis, proliferation of bile ducts and fibrosis. Spongy degeneration was observed in the brains of all eight necropsied sheep and was more severe at the cerebellar peduncles, mesencephalon, thalamus, and pons. These are suggested as the portions of election to investigate microscopic lesions of hepatic encephalopathy in sheep with chronic seneciosis. The diagnosis of Senecio spp. poisoning was based on epidemiology, clinical signs, laboratory data, necropsy and histological findings.

FBXO7-R498X mutation: phenotypic variability from chorea to early onset parkinsonism within a family.

FBXO7 mutations (PARK 15), first reported in 2008, are among the monogenic causes of early-onset parkinsonism. Classically, PARK 15 was suggested to correspond to previously described pallido-pyramidal syndrome. Here, we report clinical and genetic findings in a unique family of Kurdish origin with an FBXO7 mutation and presenting with diverse clinical phenotypes. The family consisted of 14 members (12 offspring) of whom three were affected. Two of these three siblings were examined in our clinic. DNA samples from the index case and his elder sister were subjected to homozygosity mapping and exomic sequencing. The index case had progressive speech problems, severe apathy, chorea, and tics at presentation and developed very mild parkinsonism and postural instability after 3 years. His sister had young-onset asymmetric tremor-dominant parkinsonism with some atypical features, such as early development of postural instability, tics, and tachyphemic speech. She died of an akinetic-rigid condition and had not developed chorea. A homozygous R498X mutation was found in both patients (NM_012179; chr22:31,224,440). This result was further confirmed by Sanger sequencing in both patients, their consanguineous parents, and their maternal grandfather; the latter three were found to be heterozygous for the mutation (c.C1492T; p.R498X). The family presented here broadens the clinical spectrum of parkinsonism to include tics and chorea, in addition to the parkinsonian-pyramidal phenotype, in connection with FBXO7 mutations and points to an intrafamilial phenotypic variation.

The missing tau mutation: + 15 exon 10/intron 10 boundary of MAPT stem loop structure in an Irish family with FTDP-17

WCN 2013 No: 2532 Topic: 2 — Movement Disorders The missing tau mutation: +15 exon 10/intron 10 boundary of MAPT stem loop structure in an Irish family with FTDP-17 R. Lonergan, A. McCarthy, S. O'Dowd, B. Magennis, E. Fallon, M. Spillantini, M. Hutton, T. Lynch. Neurology, Mater Misericordiae Hospital, Dublin, Ireland; Molecular Neurology, Addenbrooke's Hospital, Cambridge, UK; Eli Lilly and Company, London, UK Background: Up to 40% of families with autosomal dominant frontotemporal dementia with parkinsonism (AD FTDP-17) carry pathogenic 5′ splice site mutations in the Microtubule-Associated Protein Tau (MAPT) gene. Several stem-loop mutations of tau exon 10 were identified, but the +15 mutation remained elusive. Aim: We present a family with the ‘missing’ +15 mutation. Case: A 44 year old man developed progressive disinhibition, apathy and simultaneous amnestic syndrome. Neurological examination normal (primitive reflexes/disinhibition). Pedigree: autosomal dominant young-onset dementia. Investigations: MRI brain — moderate bitemporal atrophy; PET CT — low anterior temporal activity. CSF — raised protein: phosphorylated tau/beta-amyloid normal. Fluorescent sequencing analysis for familial tau variant: sequence variant c.915 + 15A N C, at exon 10/intron 10 boundary of MAPT gene. Identical variant in first cousin. Discussion: In 1998, Hutton described 5′ splice site mutations in tau, associated with FTDP-17, destabilising a stem-loop structure, causing alternate splicing of exon 10. The predicted +15 A N C mutation at intron 10 was ‘missing’ until now. In this unique family, the proband had profound short-term amnesia and behavioral change, suggesting atypical familial Alzheimer disease or atypical FTDP-17. Detection of novel +15 mutation clarified diagnosis of FTDP-17 and informed genetic counselling. Finding this mutation 14 years after prediction highlights value of pursuing complete family history to guide appropriate molecular genetic testing. doi:10.1016/j.jns.2013.07.549 Abstract — WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline M. Yucel, H. Akgun, S. Tasdemir, S. Alay, O. Oz, E. Eroglu, S. Demirkaya. Department of Neurology, Kasimpasa Military Hospital, Istanbul, Turkey; Department of Neurology, Etimesgut Military Hospital, Ankara, Turkey; Department of Neurology, Gulhane Military Medical Academy, Ankara, Turkey Background: Orthostatic tremor is known as a lower extremity tremor occurring when standing. When a person stands, typical high frequency (13–18 Hz) tremor develops, and disappears with walking, sitting or continuous volatile leg movement. Objective: In this report we presented a patient with tremor on the lower limbs diagnosed with Parkinson's disease. Patients and methods: A 58-year-old female patient presented to our outpatient clinic with complaints of trembling in the body when standing, lasting for 1 year. The neurological examination revealed bradykinesia of the lower and upper right limbs, rigidity and rest tremor of the right hand and trembling of the lower limbs when standing. Results: The brain MRI and the routine nerve conduction studies were normal. The superficial electrode recordings of femoris, anterior tibialis, biceps femoris muscles documented a tremor of 13 Hz. The patient was diagnosed with Parkinson's disease accompanied by orthostatic tremor and was started 2 mg of Rasagiline. Significant improvement was noted. Conclusion: We found this case worth reporting because of the rare presentation of Parkinson's disease in the literature with orthostatic symptoms as a first sign. doi:10.1016/j.jns.2013.07.550 Abstract — WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea D. Petrlenicova, M. Kucharik, M. Saling. 2nd Dept. of Neurology, Faculty of Medicine, Comenius University, University Hospital Bratislava, Bratislava,

Orthostatic tremor responding to Rasagiline

WCN 2013 No: 2532 Topic: 2 — Movement Disorders The missing tau mutation: +15 exon 10/intron 10 boundary of MAPT stem loop structure in an Irish family with FTDP-17 R. Lonergan, A. McCarthy, S. O'Dowd, B. Magennis, E. Fallon, M. Spillantini, M. Hutton, T. Lynch. Neurology, Mater Misericordiae Hospital, Dublin, Ireland; Molecular Neurology, Addenbrooke's Hospital, Cambridge, UK; Eli Lilly and Company, London, UK Background: Up to 40% of families with autosomal dominant frontotemporal dementia with parkinsonism (AD FTDP-17) carry pathogenic 5′ splice site mutations in the Microtubule-Associated Protein Tau (MAPT) gene. Several stem-loop mutations of tau exon 10 were identified, but the +15 mutation remained elusive. Aim: We present a family with the ‘missing’ +15 mutation. Case: A 44 year old man developed progressive disinhibition, apathy and simultaneous amnestic syndrome. Neurological examination normal (primitive reflexes/disinhibition). Pedigree: autosomal dominant young-onset dementia. Investigations: MRI brain — moderate bitemporal atrophy; PET CT — low anterior temporal activity. CSF — raised protein: phosphorylated tau/beta-amyloid normal. Fluorescent sequencing analysis for familial tau variant: sequence variant c.915 + 15A N C, at exon 10/intron 10 boundary of MAPT gene. Identical variant in first cousin. Discussion: In 1998, Hutton described 5′ splice site mutations in tau, associated with FTDP-17, destabilising a stem-loop structure, causing alternate splicing of exon 10. The predicted +15 A N C mutation at intron 10 was ‘missing’ until now. In this unique family, the proband had profound short-term amnesia and behavioral change, suggesting atypical familial Alzheimer disease or atypical FTDP-17. Detection of novel +15 mutation clarified diagnosis of FTDP-17 and informed genetic counselling. Finding this mutation 14 years after prediction highlights value of pursuing complete family history to guide appropriate molecular genetic testing. doi:10.1016/j.jns.2013.07.549 Abstract — WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline WCN 2013 No: 2483 Topic: 2 — Movement Disorders Orthostatic tremor responding to Rasagiline M. Yucel, H. Akgun, S. Tasdemir, S. Alay, O. Oz, E. Eroglu, S. Demirkaya. Department of Neurology, Kasimpasa Military Hospital, Istanbul, Turkey; Department of Neurology, Etimesgut Military Hospital, Ankara, Turkey; Department of Neurology, Gulhane Military Medical Academy, Ankara, Turkey Background: Orthostatic tremor is known as a lower extremity tremor occurring when standing. When a person stands, typical high frequency (13–18 Hz) tremor develops, and disappears with walking, sitting or continuous volatile leg movement. Objective: In this report we presented a patient with tremor on the lower limbs diagnosed with Parkinson's disease. Patients and methods: A 58-year-old female patient presented to our outpatient clinic with complaints of trembling in the body when standing, lasting for 1 year. The neurological examination revealed bradykinesia of the lower and upper right limbs, rigidity and rest tremor of the right hand and trembling of the lower limbs when standing. Results: The brain MRI and the routine nerve conduction studies were normal. The superficial electrode recordings of femoris, anterior tibialis, biceps femoris muscles documented a tremor of 13 Hz. The patient was diagnosed with Parkinson's disease accompanied by orthostatic tremor and was started 2 mg of Rasagiline. Significant improvement was noted. Conclusion: We found this case worth reporting because of the rare presentation of Parkinson's disease in the literature with orthostatic symptoms as a first sign. doi:10.1016/j.jns.2013.07.550 Abstract — WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea WCN 2013 No: 2514 Topic: 2 — Movement Disorders Extrapontine myelinolysis presented with sudden-onset generalised chorea D. Petrlenicova, M. Kucharik, M. Saling. 2nd Dept. of Neurology, Faculty of Medicine, Comenius University, University Hospital Bratislava, Bratislava,

A 61-year-old Diabetic And Alcoholist Male With Bilateral

A 61-year-old white right-handed man was admitted because of recent loss of weight and difficulty in swallowing solid foods. There was gradually progressive apathy, postural instability with falls backwards and cognitive deficit. His past history included controlled diabetes mellitus and arterial hypertension, tobacco smoking and heavy alcoholism. During the last two years, an unexplained bilateral contraction developed in some of his fingers. He was not a manual worker nor a guitar or piano player, and denied previous A 61-year-old diabetic and alcoholic male with bilateral ‘stiff fingers’

Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype?

Dear Sirs, From 2006, a locus on chromosome 9p21 has been associated with a large proportion of ALS and FTD [1–3]. Recently, two independent groups have identified a hexanucleotide repeat expansion in noncoding region of the C9ORF72 gene as the cause of chromosome 9p21-linked ALS-FTD [4, 5]. We report the case of a 64-year-old man who presented with a 3-year history of delusional mystic thoughts, auditive, visual, and olfactory hallucinations, and hyperreligiosity. The patient later developed progressive apathy, dysphoric mood, hyperphagia, self-care reduction, and progressive cognitive decline with motor retardation. The man's father had died at age 68 after committing suicide, and his older brother developed parkinsonism associated with behavioral disturbances at age 60 and died 2 years later. Neuropsychological assessment of this patient, performed 3 years after the onset of neurological symptoms, demonstrated bradyphrenia, marked impairment of attention and executive functions, marked constructional apraxia, mild visual and verbal long-term memory deficit, mild anomia, emotional lability, fatuity, and mild utilization behavior. Blood exams, thyroid antibodies and hormones, vitamin B12, folic acid, and TPHA were all normal. Neurological examination revealed symmetric akinetic-rigid syndrome characterized by hypomimia, dysarthria, camptocormia with anterocollis, and diffuse bradykinesia. Brain MRI documented atrophy mainly frontotemporal but with consistent posterior region involvement (Fig. 1). Perfusion SPECT with 99Tc-ethylene cystine dimer (ECD) showed a marked reduction of the uptake in the frontotemporal and parietal regions bilaterally (Fig. 1). A few months after the first neurological assessment, the patient had a rapid progression to a severe dementia and developed marked pyramidal involvement of upper and lower limbs with an inability to walk. The patient became anarthric, dysphagic, and developed constipation. The nature of the dysarthria was both pseudobulbar and extrapyramidal. Lower motor neuron signs or symptoms were not present. Later the patient was admitted to a surgical department for intestinal sub-occlusion; during the hospitalization, a pulmonary embolism (PE) occurred. The patient died 4 years after the first neurological manifestations. Mutations of TARDBP, MAPT, and PGRN genes were excluded. The patient has been found positive for a GGGGCC hexanucleotide repeat expansion in the first intron of C9ORF72 gene (>50). Our patient developed a dementia with prominent behavioral disturbances at presentation, characterized mostly by psychosis with mystic themes. The neuropsychological evaluation demonstrated a marked cognitive impairment with predominant frontal syndrome. An important involvement of visuo-spatial functions was also found (Fig. 2). This cognitive impairment, associated with multimodal hallucinations and parkinsonism, which presented before the onset of upper motor neuron signs, raised a differential diagnosis between FTD and dementia with Lewy bodies (DLB). A few cases have been reported with similar diagnostic difficulties [6]. The parkinsonism was not drug-induced. The dementia profile of our patient was consistent with a behavioral variant of FTD. He presented a positive family history for similar disturbances. Some features of our case are atypical for FTD, like psychosis, constructional apraxia associated with the frontal syndrome, atrophy, and perfusional deficit extended to posterior cortical areas. Hallucinations are possible but not common in FTD [7], whereas they are a core clinical feature in the diagnostic criteria of DLB [8]. Of note, some clinical aspects of our case have been reported in patients with ALS-FTD linked to the locus 9p21, such as the presence of parkinsonism, psychosis, visuo-spatial impairment, and brain atrophy with parietal and occipital lobe involvement [9, 10]. We propose that delusions with multimodal hallucinations at presentation, visuo-spatial dysfunction, and frontotemporal brain atrophy also involving posterior areas could be aspects of a possible distinctive phenotype of FTD-parkinsonism-upper motor neuron disease linked to the C9ORF72 gene hexanucleotide expansions. Fig. 1 a–c Brain MRI T1-weighted transversal scans showing bilateral frontotemporal and posterior cerebral areas atrophy. d–f Perfusion single-photon emission computed tomography (SPECT) with 99Tc-ethylene cystine dimer (ECD). The transversal ... Fig. 2 Severe constructional apraxia demonstrated by the copy of a simple drawing

A 2-month-old infant with vomiting, seizures, and progressive apathy

A 2-month-old infant was admitted to hospital because of recurrent vomiting for 1 week, progressive apathy, and focal seizures. The cranial MRI showed a noticeable result.

W01-03 - Neuropsychological phenotyping of genetic syndromes

Introduction Over the past years several novel microdeletion syndromes have been reported that may be associated with a specific pattern of psychological dysfunctions. Two major examples are the Kleefstra syndrome (KS) and the 17q21.31 microdeletion syndrome (17qDS). KS was originally described as the 9q subtelomeric deletion syndrome associated with marked mental retardation, specific dysmorphisms, particular sleep disturbances, and progressive deterioration and apathy, suggestive for a’neurodegenerative phenotype’. Haploinsufficiency of the EHMT1 gene is proven to be the causative factor. 17qDS comprises moderate mental retardation, dysmorphisms and various congenital anomalies. It has been suggested that the behavioural phenotype includes remarkably friendly manners. The syndrome is thought to be caused by MAPT haploinsufficiency. Objectives Neuropsychological phenotyping of KS and 17qDS. Aims Assessment of neuropsychological functions of patients with either KS or 17qDS. Methods Five patients with KS and three patients with 17qDS were extensively investigated by means of broad band neurocognitive instruments as well as specific rating scales. Results The behavioural phenotype of KS was characterized by behavioural and motor deficiencies that become apparent at adolescence and increase over time. Motor symptoms could be attributed to a progressive apathy syndrome. In 17qDS the neuropsychological phenotype comprised, as compared to a matched control group, less social fear and more approaching behaviour. Conclusions In both syndromes, neuropsychological examination demonstrates specific patterns of (cognitive) development and social interaction. These findings further clarify the genotype-phenotype relation and are of importance for the establishment of an individualized behavioural and clinical management program.

Intracranial phosphaturic mesenchymal tumor, mixed connective tissue variant presenting without oncogenic osteomalacia

Background:Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT) is a rare tumor typically occurring in soft tissues and bone, causing oncogenic (tumor-induced) osteomalacia (TIO) through secretion of the phosphaturic hormone, fibroblast growth factor-23 (FGF-23). Rare tumors identical to PMTMCT occur without known TIO. Intracranial localization of PMTMCT is extremely rare, with only two cases reported in the literature. We present a very unusual case of a patient with an intracranial PMTMCT that presented with neurologic changes without osteomalacia.Case Description:A 67-year-old woman presented with progressive incontinence, apathy, and abulia after having undergone a total knee replacement 1 month earlier. Imaging disclosed a large left frontal anterior fossa mass. She underwent uncomplicated surgical resection of this tumor. Surprisingly, histopathology suggested PMTMCT. Reverse transcription polymerase chain reaction (RT-PCR) assay demonstrating FGF-23 expression in the tumor confirmed the diagnosis. Serum FGF-23 levels postoperatively were normal and she had no clinical or laboratory evidence of osteomalacia or phosphaturia.Conclusion:This report should serve to alert clinicians to the possibility that PMTMCT can be included in the differential diagnosis of intracranial masses even in the absence of tumor-induced osteomalacia.

Vaccinia viruses isolated from cutaneous disease in horses are highly virulent for rabbits

Two genotypically distinct Vaccinia viruses (VACV), named P1V and P2V, were isolated from an outbreak of cutaneous disease in horses in Southern Brazil. We herein investigated the susceptibility of rabbits, a proposed animal model, to P1V and P2V infection. Groups of weanling rabbits were inoculated intranasally (IN) with P1V or P2V at low (102.5 TCID50), medium (104.5TCID50), or high titer (106.5TCID50). Rabbits inoculated with medium and high titers shed virus in nasal secretions and developed serous to hemorrhagic nasal discharge and severe respiratory distress, followed by progressive apathy and high lethality. Clinical signs appeared around days 3–6 post-inoculation (pi) and lasted up to the day of death or euthanasia (around days 5–10). Virus shedding and clinical signs were less frequent in rabbits inoculated with low virus titers. Viremia was detected in all groups, with different frequencies. Viral DNA was detected in the feces of a few animals inoculated with P1V and P2V, low titer, and with P2V at high titer. Gross necropsy findings and histological examination showed diffuse interstitial fibrousing pneumonia with necrosuppurative bronchopneumonia and intestinal liquid content. Neutralizing antibodies were detected in all inoculated animals surviving beyond day 9pi. These results show that rabbits are highly susceptible to VACV isolated from horses, and develop severe respiratory and systemic disease upon IN inoculation. Thus, rabbits may be used to study selected aspects of VACV infection and disease.

Morvan chorea and agrypnia excitata: When video-polysomnographic recording guides the diagnosis

Morvan chorea is an antibody-mediated limbic encephalopathy characterized by severe insomnia, mental confusion, hallucinations, enacted dreams, hyperhidrosis, and neuromyotonia. In a 78 years old man presenting with progressive insomnia apathy and depression, a video-polysomnogram documented enacted dreams mimicking daily life activity (oneiric stupor). This finding led us to perform a search for serum antibodies to voltage-gated K+ channels, which was positive. A diagnosis of Morvan chorea was done. The patient underwent plasma exchange with complete resolution of the clinical picture. Oneiric stupor may represent a useful precocious diagnostic marker in Morvan chorea.