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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282X

Arq. Neuro-Psiquiatr. vol.70 no.3 São Paulo Mar. 2012 



Behavioral changes on amyotrophic lateral sclerosis (ALS): a case of ALS/FTD TDP-43 proteinopathy


Deterioração comportamental na esclerose lateral amiotrófica (ELA): um caso de proteinopatia TDP-43 associada à ELA e demência frontotemporal



Bruno Lopes dos SantosI; Guilherme Riccioppo RodriguesI; Vitor TumasI; José Eymard Homem PittellaII

IMovement Disorders and Cognitive Neurology Unit, Department of Neuroscience and Behavior Sciences, Medical School of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto SP, Brazil
IIDepartment of Pathology, Medical School of Ribeirão Preto, USP, Ribeirão Preto SP, Brazil




The frontotemporal dementia (FTD) is the second most common form of dementia in patients younger than 65 years, and its behavioral variant (bvFTD) is the most prevalent form1,2. During the last years, the overlapping between FTD and amyotrophic lateral sclerosis (ALS) has been frequently recognized, with symptoms of FTD preceding ALS and vice-versa. Herein, we report a case of ALS, which afterwards presented psychotic and behavioral symptoms, whose neuropathological diagnosis was compatible with bvFTD-ALS with TAR DNA-binding protein 43 (TDP-43) inclusion3.



A 58-year-old man was admitted in our Emergency Unit with a one-year history of progressive weakness of limbs, associated with dysarthria, dysphonia, difficulty to close mouth and hands atrophy. Four days before admission, he developed dyspnea and acute respiratory failure. In the hospital, it was seen generalized weakness, global hyperreflexia, fasciculations on right arm, no sensory abnormalities, and the electroneuromyography showed chronic and acute denervation signs in cranial, cervical and lumbosacral segments, confirming the diagnosis of amyotrophic lateral sclerosis. As the patient had no social and economic home support, he lived the rest of his life hospitalized, with mechanic ventilation. In the first year after admission, the patient showed anxious and depressive symptoms, associated with a permanent refusal of his condition, with great hopes of cure, even after exhaustive explanation about the diagnosis. This behavior was considered as mechanism of denial.

Progressively, the patient became hostile to nurses and physicians, blaming his disease to clinical staff, with frequent verbal aggression. He said that the family was visiting him, but there were no proof of these visits. After 2 years of hospitalization, the agressivity worsened, without improvement with antidepressants drugs. The patient affirmed that the disease could be resolved with antibiotic, but the physicians did not want to treat him. In his last months, the persecutory delusions became more intense, associated with visual hallucinations. As there were no clinical signs of delirium, a psychotic delusional disorder was diagnosed and neuroleptic medications were started. His psychiatric status progressively worsened, with auditory hallucinations and physical aggression to the clinical staff. After 2 years and 9 months of hospitalization, the patient died by asphyxia by tracheal blood clot.

On necropsy (Fig), it was seen moderate reduction in hypoglossus nucleus and in anterior column of spinal cord motor neurons, and myelin pallor on anterior and lateral funiculi, sparing posterior funiculus (Fig C), and the brain showed spongiosis in layer II, predominantly in temporal cortex (Fig A and B). The immunoreactivity to protein tau was negative, but there were granular neuronal intracytoplasmatic inclusions and dystrophic neurites positive to ubiquitin and TDP-43 (subtype 3 from Mackenzie et al.)4.



The discovery of TDP-433-5 in brains of patients with the association FTD-ALS has improved the comprehension of its pathophysiology. This specific phenotype often shows the presence of delusions and hallucinations1, as seen in our case, and these symptoms should draw our attention to the possibility of TDP-43 proteinopathy on motor neuron disease. As the patient was hospitalized during almost 3 years, it was possible to register details of his behavioral degeneration.



We thank Dr. Lea Tenenholz Grinberg, MD, PhD, UCSF Memory and Aging Center, USA, for immunohistochemical reaction to TDP-43.



1. Lillo P, Garcin B, Hornberger M, Bak TH, Hodges JR. Neurobehavioral features in frontotemporal dementia with amyotrophic lateral sclerosis. Arch Neurol 2010;67:826-830.         [ Links ]

2. Piguet O, Hornberger M, Mioshi E, Hodges JR. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol 2011;10:162-172.         [ Links ]

3. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130-133.         [ Links ]

4. Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 2010;9:995-1007.         [ Links ]

5. Geser F, Lee VMY, Trojanowski JQ. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 2010;30:103-112.         [ Links ]



Bruno Lopes dos Santos; Setor de Distúrbios do Movimento e Neurologia Cognitiva, Departamento de Neurociências e Ciências Comportamentais, Faculdade de Medicina de Ribeirão Preto, USP; Av. Bandeirantes 3900; 14049-900 Ribeirão Preto SP - Brasil;

Received 26 June 2011;
Received in final form 28 September 2011;
Accepted 05 October 2011

Conflict of interest:
There is no conflict of interest to declare.

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