Clinical Neurological Signs Research Articles

Risk factors for development of neurologic disease after experimental exposure to equine herpesvirus-1 in horses

To identify risk factors associated with development of clinical neurologic signs in horses exposed to equine herpesvirus-1 (EHV-1). 36 adult horses. Blood samples collected before and after challenge inoculation with nonneuropathogenic or neuropathogenic EHV-1 were analyzed for leukocyte-associated viremia, serum neutralizing antibody, and EHV-1-specific cytotoxic T-lymphocyte precursors (CTLPs). Associations between variables and neurologic disease and correlations between age category or breed and development of neurologic disease were examined. 9 horses developed CNS signs (ataxia, hind limb paresis or paralysis, bladder atony, or recumbency). Neurologic deficits were correlated with infection by a neuropathogenic strain of EHV-1, age>20 years, high postexposure viremic load, and low preexposure concentration of CTLPs. No significant correlations were observed between preinfection titers or horse breed and postinfection development of neurologic signs. Horses with high concentrations of preexisting CTLPs, regardless of age, strain of virus, or titer, were more likely to control the magnitude of postinfection leukocyte-associated viremia and subsequent development of neurologic disease; therefore, CTLPs appear to be a critical requirement for protective immunity against EHV-1-induced myeloencephalopathy. The importance of achieving immunity related to high concentrations of vaccine-induced CTLPs in horses at high risk for exposure to neuropathogenic strains of EHV-1 is indicated.

Detection of raised intracranial pressure by ultrasound measurement of optic nerve sheath diameter in African children

To evaluate optic nerve sheath (ONS) ultrasound as a non-invasive method of detecting raised intracranial pressure (ICP) and to establish normal ONS diameter data for African children. Children with acute neurological disease admitted to the Paediatric Department of Queen Elizabeth Central Hospital, Malawi had ultrasound measurements of ONS diameter. Controls were children admitted to the same department with non-neurological disease. The mean of three measurements of the ONS diameter was used for analysis. Children were assessed for clinical signs of raised ICP. Patients had CT brain scans if required for their normal clinical care. In 14 children with neurological disease and clinical signs suggestive of raised ICP, the mean ONS diameter was 5.4 mm (range 4.3-6.2 mm). Radiological signs on CT scans substantiated the presence of raised ICP in eight (all those scanned). In seven children with neurological disease but no specific signs of raised ICP the mean ONS diameter was 3.6 mm (range 2.8-4.4 mm). None of four of these patients examined by CT scan had signs of elevated ICP. The mean ONS diameter in 30 controls without neurological disease was 3.5 mm (range 2.5-4.1 mm). If 4.2 mm is taken as the upper limit of normal the sensitivity and specificity of this test for elevated ICP is 100% and 86%, respectively. ONS ultrasound is an accurate method for detecting raised ICP that can be applied in a broad range of settings. It has the advantages of being a non-invasive, bedside test, which can be repeated multiple times for re-evaluation.

A large dumbbell glossopharyngeal schwannoma involving the vagus nerve: a case report and review of the literature

IntroductionSchwannoma arising from the glossopharyngeal nerve is a rare intracranial tumor. Fewer than 40 cases have been reported. Accurate pre-operative diagnosis and optimal treatment are still difficult.Case presentationWe present one case of schwannoma originating from the ninth cranial nerve with palsies of the trigeminal nerve, facial-acoustic nerve complex, and vagus nerve in addition to ninth nerve dysfunction. Magnetic resonance imaging showed tumors located in the cerebellopontine angle with extracranial extension via the jugular foramen, with evident enhancement on post-contrast scan. Surgical management single-staged with the help of gamma knife radiosurgery achieved total removal.ConclusionGlossopharyngeal schwannoma is devoid of clinical symptoms and neurological signs. High resolution magnetic resonance imaging may play a key role as an accurate diagnostic tool. A favorable option of approach and appropriate planning of surgical strategy should be the goal of operation for this benign tumor.

An Intensive Approach in the Treatment of Clinical Equine Protozoal Myeloencephalitis

Equine protozoal myeloencephalitis (EPM) is a serious parasitic disease of horses producing neurologic clinical signs. Sarcocystis neurona is an incriminated pathogen. If approximately 50% of US horses are seropositive but only 0.5 to 1% become clinically affected, there is a suspected immunologic influence whether a horse is S. neurona-exposed or has clinical EPM syndrome. This report presents a treatment of 28 performance horses that were serum immunoblot positive for exposure to S. neurona. This patient population was in full athletic competition, travel, or training with associated stress. We attempted to (1) improve the immunologic status of the horse, (2) protect it against inflammatory reactions, and (3) provide medication to kill the protozoa. The cell-mediated immunity was stimulated by transfer factor in the feed for 37 days. The inflammatory reactions of treatment crises from antiprotozoal activity were prevented by MicroLactin (a neutrophil-activation inhibitor) in feed for 28 days concurrently. The antiprotozoal drug ponazuril was given concurrently for 28 days. Gait abnormalities, stumbling, and behavior change were the most frequent and combined clinical signs before treatment. There were 82% (23/28) treatable horses that were back at work, including five horses that were in physical rehabilitation under saddle. Five severely affected horses were not helped by therapy.

Monocrotaline pyrrol is cytotoxic and alters the patterns of GFAP expression on astrocyte primary cultures

Dehydromonocrotaline (DHMC) is the main monocrotaline active cytochrome P450's metabolite, and has already been assessed in the CNS of experimentally intoxicated rats. DHMC effects were here investigated toward rat astroglial primary cultures regarding cytotoxicity, morphological changes and regulation of GFAP expression. Cells, grown in DMEM supplemented medium, were treated with 0.1-500 microM DHMC, during 24- and 72-h. According to MTT and LDH tests, DHMC was toxic to astrocytes after 24-h exposure at 1 microM, and induced membrane damages at 500 microM. Rosenfeld dying showed hypertrophic astrocytes after 72-h exposure to 0.1-1 microM DHMC. GFAP immunocytochemistry and western immunoblot revealed an increase of GFAP labelling and expression, suggesting an astrogliotic reaction to low concentrations of DHMC. At higher concentrations (10-500 microM), astrocytes shrank their bodies and retracted their processes, presenting a more polygonal phenotype and a weaker expression on GFAP labelling Nuclear chromatin staining by Hoechst-33258 dye, revealed condensed and fragmented chromatin in an important proportion (+/-30%) of the astrocytes exposed to 100-500 microM DHMC, suggesting signs of apoptosis. Our results confirm a cytotoxic and dose-dependent effect of DHMC on cultures of rat cortical astrocytes, leading to apoptotic figures. These effects might be related to the neurological damages and clinical signs observed in animals intoxicated by Crotalaria.

Isolation of a novel viral agent associated with porcine reproductive and neurological syndrome and reproduction of the disease

Disease outbreaks characterized by reproductive failure and/or neurologic disorders, which are commonly referred as “Porcine Reproductive and Neurologic Syndrome (PRNS)”, were observed in many swine farms in Iowa and other states. Although an infectious cause was suspected to account for the disease, no conclusive diagnosis had been reached with respect to conventional infectious agents. Extensive laboratory diagnostic investigation on suspect cases repeatedly resulted in the isolation of a cytopathic enveloped virus of 50–60 nm in size from nervous and second lymphoid tissues and sera and, to reflect its unknown identity, named “Virus X”. The presence of virus particle with morphological characteristics similar to Virus X in tissues from affected animals was also observed on thin-section positive-staining electron microscopy. Isolates of Virus X were not readily recognized by antibodies raised against any known viruses pathogenic to swine but by antisera collected from animals surviving clinical episode, indicating that Virus X is likely a previously unrecognized agent. Pregnant sows experimentally inoculated with Virus X (ISUYP604671) or homogenate (filtrate) of tissues from a clinically affected animal developed clinical signs and pathological changes similar to field observations including the loss of pregnancy. Furthermore, caesarian-derived, colostrum-deprived young pigs developed mild encephalomyelitis lesions in brains after experimental inoculation with the virus or the tissue homogenate although clinical neurologic signs were not observed. More importantly, Virus X was re-isolated from all inoculated animals while control pigs remained negative for the virus during the study. Collectively, Virus X is a novel viral agent responsible for PRNS and remains to be further characterized for taxonomical identity.

Clinical outcome of congenital extrahepatic portosystemic shunt attenuation in dogs aged five years and older: 17 cases (1992–2005)

To assess the outcome of extrahepatic portosystemic shunt (EHPSS) treatment in dogs aged 5 years and older. Retrospective case series. 17 client-owned dogs. Medical records for dogs (> or = 5 years old) that underwent surgical attenuation of an EHPSS (1992 through 2005) were evaluated; data, including clinical signs, clinicopathologic findings, surgical procedure, and outcome, were recorded. Follow-up information was obtained via patient examination or telephone interview with veterinarians and owners. Dogs (5 to 9 years old [median age, 6.6 years]) had neurologic (n = 12), urinary tract (8), and gastrointestinal tract (6) EHPSS-associated clinical signs. Serum bile acids and ammonia concentrations were abnormal in all evaluated dogs. Treatment of EHPSSs included complete (n = 6 dogs) or partial (2) suture attenuation or ameroid constrictor placement (9). Two dogs died following surgery. Follow-up information (6 to 120 months) was available for 13 dogs. Deaths were attributable to heart failure (n = 1), bacterial hepatitis (2; with pyelonephritis in 1 dog), and unknown causes (3). At a median of 23 and 25 months, serum bile acids concentrations had almost normalized in 5 of 8 dogs and ammonia concentrations were within reference limits in 3 of 5 dogs, respectively; dogs with abnormal liver function test results had no associated clinical signs. Median long-term survival time was 72 months. Attenuation of EHPSS in > or = 5-year-old dogs ameliorated signs of liver dysfunction in surviving dogs, although return of normal liver function occurred less frequently than expected.

Fractures of the cervical vertebral odontoid in four horses and one pony

Four horses and one pony, ranging in age from one to 11 years, were diagnosed with two different types of odontoid peg fractures. Their clinical signs included reluctance to move...

A Case of Frontotemporal Lobar Degeneration (FTLD) With Panic Attack as the First Symptom

A Case of Frontotemporal Lobar Degeneration (FTLD) With Panic Attack as the First Symptom

The host-parasite relationship in pregnant cattle infected withNeospora caninum

The protozoan parasite Neospora caninum is an important cause of reproductive disease in cattle worldwide. The dog is a definitive host for the parasite and the oocyst stage, shed in the faeces, is a source of infection for cattle through consumption of contaminated feed or water. In addition, transplacental transmission of N. caninum is a very efficient means of the parasite infecting a new host and this can occur in successive pregnancies and over several generations. Neospora parasites may cause disease during pregnancy resulting in death of the foetus or birth of live congenitally infected calves that may show some neurological clinical signs at birth. The stage of pregnancy at which infection/parasitaemia occurs is an important factor in determining disease severity. Neospora infection in the first trimester of pregnancy may have more severe consequences for the foetus compared with infection occurring in the final trimester. The host-parasite relationship during pregnancy is a fascinating interaction and research in this area will improve understanding of disease pathogenesis and the various consequences of the host immune response, being host-protective, parasite protective and contributing to disease pathology. Pregnancy poses an interesting problem for the immune system of the dam as she is essentially carrying a semi-allogeneic tissue graft (the foetus) without immunological rejection taking place. To facilitate the pregnancy the cytokine environment in the placenta favours the regulatory Th-2-type cytokines, whose role is to counteract the pro-inflammatory Th1-type immune responses. Protective immunity to N. caninum, similar to many other intracellular parasites, involves Th1-type immune responses, which may pose problems for the dam trying to control a Neospora infection during pregnancy. This paper will discuss the host-parasite relationship at different stages of gestation in pregnant cattle and review the implications of this research for our understanding of disease pathogenesis, parasite transmission and host protection.

Glutamate Receptor Expression in Multiple Sclerosis Lesions

Blockade of receptors for the excitatory neurotransmitter glutamate ameliorates neurological clinical signs in models of the CNS inflammatory demyelinating disease multiple sclerosis (MS). To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca(++)-permeable ionotropic AMPA receptor subunit, was up-regulated on oligodendrocytes in active MS lesion borders, but Ca(++)-impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT-1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5-7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. Thus, reactive astrocytes in MS white matter lesions are equipped for a protective role in sequestering and metabolizing extracellular glutamate. However, they may be unable to maintain glutamate at levels low enough to protect oligodendrocytes rendered vulnerable to excitotoxic damage because of GluR1 up-regulation.

Bovine herpesvirus 5 detection by virus isolation in cell culture and multiplex-PCR in central nervous system from cattle with neurological disease in Brazilian herds

Bovine herpesvirus 5 (BoHV-5) is an important cause of meningoencephalitis in young and adult cattle. The multiple etiology of neurological disturbances in cattle makes the quick and conclusive diagnosis of BoHV-5 infection important for animal and public health, mainly because of herbivore rabies that is endemic in Brazilian cattle herds. The objective of this retrospective study was to use a multiplex-polymerase chain reaction (multiplex-PCR) for BoHV-5 and BoHV-1 glycoprotein C gene detection from stored central nervous system (CNS) tissue fragments of cattle with neurological clinical signs. Forty-seven frozen CNS samples of young and adult cattle from 31 herds in three Brazilian geographical regions (South, Southeast, and Center-west) were evaluated. Eighteen (38.3%) of these CNS samples were BoHV-positive by virus isolation in cell culture. By multiplex-PCR 30 (63.8%) CNS samples were BoHV-5 positive. All 18 positive samples by virus isolation were confirmed as BoHV-5 by the multiplex-PCR, that provided a increase of 25.5% (12/47) in the BoHV-5 diagnosis rate. BoHV-1 was not detected in any CNS sample. This retrospective study demonstrated the wide regional distribution of BoHV-5 infection in Brazilian cattle herds since positive results were obtained in CNS samples of cattle with neurological disease from Parana, Sao Paulo, Minas Gerais, Mato Grosso, and Mato Grosso do Sul States.

Disease Duration Determines Canine Distemper Virus Neurovirulence

The Morbillivirus hemagglutinin (H) protein mediates attachment to the target cell. To evaluate its contribution to canine distemper virus neurovirulence, we exchanged the H proteins of the wild-type strains 5804P and A75 and assessed the pathogenesis of the chimeric viruses in ferrets. Both strains are lethal to ferrets; however, 5804P causes a 2-week disease without neurological signs, whereas A75 is associated with a longer disease course and neurological involvement. We observed that both H proteins supported neuroinvasion and the subsequent development of clinical neurological signs if given enough time, demonstrating that disease duration is the main neurovirulence determinant.

Aspectos clinicopatológicos de 620 casos neurológicos de cinomose em cães: Clinicopathological features in 620 neurological cases of canine distemper

Os protocolos de 5.361 necropsias de cães realizadas no Laboratório de Patologia Veterinária da Universidade Federal de Santa Maria de 1965 a 2006 foram revisados à procura de casos de cinomose. Seiscentos e oitenta e três casos (12,7%) da doença foram encontrados, dos quais 620 apresentavam sinais neurológicos. Desses 620, os seguintes dados foram recuperados para cada caso: idade, sinais clínicos, achados histopatológicos e presença ou não de doença concomitante. Faixas etárias foram classificadas como filhotes (até 1 ano), adultos (de 1 a 9 anos) e idosos (10 anos de idade ou mais). Lesões histológicas foram observadas em 565 (91,1%) dos 620 casos com sinais neurológicos de cinomose e em 554 desses casos a idade foi registrada no protocolo com a seguinte distribuição por faixa etária: 45,9% de filhotes, 51,4% de adultos e 2,7% de idosos. Os sinais neurológicos compreendiam um largo espectro de distúrbios motores, posturais e do comportamento, que podiam ocorrer juntos ou individualmente. Os sinais clínicos mais freqüentes foram mioclonia (38,4%), incooordenação motora (25,0%), convulsões (18,5%) e paraplegia (13,4%). Em 98,4% dos 565 cães com alterações histopatológicas no encéfalo, foram observadas desmielinização, encefalite não-supurativa ou uma combinação dessas duas lesões. Corpúsculos de inclusão foram observados em diferentes células de 343 dos 565 cães com alterações histopatológicas no encéfalo. Em 170 (49,6%) o tipo celular com inclusão não foi mencionado no protocolo; nos restantes, as inclusões foram vistas em astrócitos (94,8% dos casos), neurônios (3,5%), oligodendrócitos (1,1%) e células do epêndima (0,6%). Levando em consideração o tipo de lesões e as faixas etárias, casos com desmielinização e encefalite não-supurativa ocorreram em 40,0% dos filhotes, 51,2% dos adultos e 72,7% dos cães idosos. Somente desmielinização foi descrita em 48,4% dos filhotes, 41,3% dos adultos e 35,7% dos cães idosos. Somente encefalite não-supurativa foi descrita em 11,6% dos filhotes, 7,5% dos adultos e 7,1% dos cães idosos.

Estudo histológico e imunoistoquímico do sistema nervoso central de cães naturalmente infectados por Leishmania (Leishmania) chagasi

O objetivo do presente estudo foi caracterizar as alterações histopatológicas e detectar por imunoistoquímica, a presença de formas amastigotas de Leishmania no sistema nervoso central de cães com e sem sintomatologia neurológica da doença. Foram utilizados dois grupos de animais; o primeiro foi composto de 18 cães com leishmaniose visceral sem evidência clínica de envolvimento neurológico, e o segundo, composto de 21 cães com leishmaniose visceral e sintomas neurológicos. As mais freqüentes alterações histopatológicas encontradas no sistema nervoso central de cães de ambos os grupos foram degeneração neuronal com neuronofagia, gliose, leptomeningite, congestão vascular, presença de infiltrado linfoplasmocitário perivascular e áreas de microhemorragia. Não foram observadas marcações antigênicas para formas amastigotas de Leishmania em nenhum fragmento do sistema nervoso central de cães de ambos os grupos; entretanto, a maioria deles apresentava marcação em parede de vasos sangüíneos, o que sugere a presença de antígenos parasitários circulantes.

Schizo-obsessive and obsessive-compulsive disorder: Comparison of clinical characteristics and neurological soft signs

The purpose of the study was to examine whether schizophrenia with obsessive-compulsive disorder (OCD) represents a severe form of OCD-spectrum disorders on the basis of neurological soft signs (NSS) and obsessive-compulsive (OC) symptoms. Sixteen patients with OCD-schizophrenia, 25 OCD patients and 23 healthy controls (HC) were studied. Scales for the Assessment of Positive (SAPS) and Negative Symptoms (SANS), Clinical Global Impressions Scale and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess the schizophrenic and OC symptomatology. NSS were evaluated with the Neurological Evaluation Scale (NES). OCD-schizophrenics had significantly higher scores on total NES than HC. The patients with OCD were more likely to have total Y-BOCS and subscale scores of compulsions than patients with OCD-schizophrenia. The rate of symmetry obsessions and cleaning/washing compulsions were significantly higher in patients with OCD compared to OCD-schizophrenics. We have found no correlation of OC symptoms with schizophrenic symptomatology. Our findings may suggest that OCD-schizophrenia is a distinct subtype of schizophrenia, not a more severe form of OCD-spectrum disorder.

Assessment of calcium-binding proteins (Parvalbumin and Calbindin D-28K) and perineuronal nets in normal and scrapie-affected adult sheep brains

Scrapie is a prion disease in small ruminants that manifests itself with neurological clinical signs amongst which are ataxia and tremors. These signs can be explained partially by an imbalance in central inhibitory innervation. The study of the brain's inhibitory neuronal GABAergic populations and of their extracellular matrix has been used to define, in part, the pathogenesis of human prion diseases and scrapie models in rodents. The brain's distribution of neuronal GABAergic subpopulations has been monitored carefully using, as markers, antibodies against the calcium binding proteins parvalbumin and calbindin D-28K. The distribution of this perineuronal net marker was evaluated by means of affinity histochemistry with W. floribunda agglutinin. These techniques were performed on the brains of nine scrapie-positive sheep and on four infection-free sheep. These animals had undergone previously a clinical follow-up as well as a lesion profile and an immunohistochemical profile of the scrapie-associated prion protein deposition in the brain. The study of calcium-binding proteins revealed an alteration of the parvalbumin positive GABAergic neuronal subpopulation. In scrapie-positive cases, a reduction in stained neuronal perykaria was observed, along with a marked reduction of neurite labelling. This finding was noticeable in regions such as the neocortex, particularly the motor frontal cortex, and was concomitant with a moderate PrPsc deposition and a mild degree of lesion. No changes were observed in the extracellular matrix study. The results of the present study provide a partial explanation for the mechanisms of scrapie clinical signs due to a disturbance of the parvalbumin-positive inhibitory neuronal population.

Genome Microevolution of Chikungunya Viruses Causing the Indian Ocean Outbreak

BackgroundA chikungunya virus outbreak of unprecedented magnitude is currently ongoing in Indian Ocean territories. In Réunion Island, this alphavirus has already infected about one-third of the human population. The main clinical symptom of the disease is a painful and invalidating poly-arthralgia. Besides the arthralgic form, 123 patients with a confirmed chikungunya infection have developed severe clinical signs, i.e., neurological signs or fulminant hepatitis.Methods and FindingsWe report the nearly complete genome sequence of six selected viral isolates (isolated from five sera and one cerebrospinal fluid), along with partial sequences of glycoprotein E1 from a total of 127 patients from Réunion, Seychelles, Mauritius, Madagascar, and Mayotte islands. Our results indicate that the outbreak was initiated by a strain related to East-African isolates, from which viral variants have evolved following a traceable microevolution history. Unique molecular features of the outbreak isolates were identified. Notably, in the region coding for the non-structural proteins, ten amino acid changes were found, four of which were located in alphavirus-conserved positions of nsP2 (which contains helicase, protease, and RNA triphosphatase activities) and of the polymerase nsP4. The sole isolate obtained from the cerebrospinal fluid showed unique changes in nsP1 (T301I), nsP2 (Y642N), and nsP3 (E460 deletion), not obtained from isolates from sera. In the structural proteins region, two noteworthy changes (A226V and D284E) were observed in the membrane fusion glycoprotein E1. Homology 3D modelling allowed mapping of these two changes to regions that are important for membrane fusion and virion assembly. Change E1-A226V was absent in the initial strains but was observed in >90% of subsequent viral sequences from Réunion, denoting evolutionary success possibly due to adaptation to the mosquito vector.ConclusionsThe unique molecular features of the analyzed Indian Ocean isolates of chikungunya virus demonstrate their high evolutionary potential and suggest possible clues for understanding the atypical magnitude and virulence of this outbreak.

The human cerebral cortex on MRI: value of the coronal plane

The evaluation of different cortical areas of the cerebral cortex has been analyzed using MRI of 50 normal subjects without any neurological symptoms. This analysis has been made with different spin echo and gradient echo in T1 or T2 in three different planes: horizontal, sagittal and coronal. The most accurate plane to define important cortical areas such as Broca area, Wernicke area, temporal cortex at the level of the superior temporal sulcus, angular gyrus, supra marginal gyrus, hippocampal and parahippocampal cortices as well as that of the parieto or temporo-occipital areas is the coronal plane. Evidently it must be correlated with the other orthogonal planes. To be compared with the main Atlas of Neuroanatomy these sections must be perpendicular or parallel to the plane passing through the anterior and posterior commissures. MRI of patients with neurological disorders must have, as a routine, a series of MR sections performed in the coronal plane, as well as in horizontal and sagittal ones. The coronal plane is certainly the most precise to evaluate these areas involved in language, memory, visuo spatial or behavioral functions. It must be always compared with the rest of the neuroradiological examination and correlated with the clinical neurological signs.

Ziprasidone Overdose: Cases Recorded in the Database of Pfizer-Spain and Literature Review

Ziprasidone is an atypical antipsychotic with a highly specific receptorbinding profile that has been shown to be effective for both positive and negative symptoms of schizophrenia. The agent has been associated with a low frequency of extrapyramidal symptoms and sedative and anticholinergic effects. Four cases of acute ziprasidone overdose were recorded in the database of the department of pharmacovigilance of Pfizer-Spain from January 2003 (when ziprasidone was first marketed in Spain) to October 2004. The doses taken were 780, 1120, 4400, and 4480 mg. In two cases, an excessive ingestion of other drugs such as benzodiazepines and sedative hypnotics was also noted. None of the four cases showed cardiac adverse effects, and the QTc interval was within the normal range in all patients. No relevant neurologic clinical signs were observed, except for mild drowsiness in three cases. Evaluation of these four cases, as well as review of the literature, showed that an overdose of ziprasidone alone, in patients without risk factors that contraindicate its use, is relatively safe.