Multifocal Neurological Signs Research Articles

Broadly Reactive Pan-Paramyxovirus Reverse Transcription Polymerase Chain Reaction and Sequence Analysis for the Detection of Canine Distemper Virus in a Case of Canine Meningoencephalitis of Unknown Etiology

Despite the immunologic protection associated with routine vaccination protocols, Canine distemper virus (CDV) remains an important pathogen of dogs. Antemortem diagnosis of systemic CDV infection may be made by reverse transcription polymerase chain reaction (RT-PCR) and/or immunohistochemical testing for CDV antigen; central nervous system infection often requires postmortem confirmation via histopathology and immunohistochemistry. An 8-month-old intact male French Bulldog previously vaccinated for CDV presented with multifocal neurologic signs. Based on clinical and postmortem findings, the dog's disease was categorized as a meningoencephalitis of unknown etiology. Broadly reactive, pan-paramyxovirus RT-PCR using consensus-degenerate hybrid oligonucleotide primers, combined with sequence analysis, identified CDV amplicons in the dog's brain. Immunohistochemistry confirmed the presence of CDV antigens, and a specific CDV RT-PCR based on the phosphoprotein gene identified a wild-type versus vaccinal virus strain. This case illustrates the utility of broadly reactive PCR and sequence analysis for the identification of pathogens in diseases with unknown etiology.

The cat with neurological manifestations of systemic disease. Key conditions impacting on the CNS.

Practical relevanceA number of systemic diseases are associated with neurological deficits. Most systemic diseases that impact on the nervous system result in multifocal neurological signs; however, isolated deficits can also be observed. This article reviews the clinical signs, pathophysiology, diagnosis, treatment and prognosis of four important systemic diseases with neurological consequences: feline infectious peritonitis, toxoplasmosis, hypertension and hepatic encephalopathy.Clinical challengesEarly recognition of systemic signs of illness in conjunction with neurological deficits will allow for prompt diagnosis and treatment. While neurological examination of the feline patient can undoubtedly be challenging, hopefully the accompanying articles in this special issue will enable the clinician to approach these cases with more confidence.Evidence baseThe veterinary literature contains numerous reports detailing the impact of systemic disease on the nervous system. Unfortunately, very few references provide detailed descriptions of large cohorts of affected cats. This review summarises the literature underpinning the four key diseases under discussion.

Metastatic gastric adenocarcinoma to the cerebrospinal fluid: A report of three cases

Neoplastic meningitis is seen in five to ten percent of patients with solid tumors and is characterized by multifocal neurological signs and symptoms. The diagnosis is established by imaging, cerebrospinal fluid (CSF) cytology, and radioisotope CSF flow studies. Gastric adenocarcinoma is a rare cause of neoplastic meningitis. We review here CSF cytology results from our Oncology center obtained over two years and report three cases of gastric adenocarcinoma with cytologically positive CSF.

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the CNS characterized by a widespread demyelination that predominantly involves the white matter of the brain and spinal cord. The condition is usually precipitated by a viral infection or vaccination. The presenting features include an acute encephalopathy with multifocal neurologic signs and deficits. Children are preferentially affected. In the absence of specific biologic markers, the diagnosis of ADEM is still based on the clinical and radiologic features. Although ADEM usually has a monophasic course, recurrent or multiphasic forms have been reported, raising diagnostic difficulties in distinguishing these cases from multiple sclerosis (MS). The International Pediatric MS Study Group proposes uniform definitions for ADEM and its variants. We discuss some of the difficulties in the interpretation of available literature due to the different terms and definitions used. In addition, this review summarizes current knowledge of the main aspects of ADEM, including its clinical and radiologic diagnostic features, epidemiology, pathogenesis, and outcome. An overview of ADEM treatment in children is provided. Finally, the controversies surrounding pediatric MS and ADEM are addressed.

Susac's syndrome: 1975–2005 microangiopathy/autoimmune endotheliopathy

Susac's syndrome (SS) consists of the clinical triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss. It is due to a microangiopathy affecting the precapillary arterioles of the brain, retina, and inner ear (cochlea and semicircular canals). Women are more commonly affected than men (3:1); the age of onset ranges from 9 to 58 years; but young women between the ages of 20 and 40 are most vulnerable. The encephalopathy is almost always accompanied by headache which may be the presenting feature. Multifocal neurological signs and symptoms, psychiatric disturbances, cognitive changes, memory loss, and confusion may rapidly progress to dementia. The MRI shows a distinctive white matter disturbance that always affects the corpus callosum. The central callosal fibers are particularly vulnerable and central callosal holes develop as the active lesions resolve. Linear defects (spokes) and rather large round lesions (snowballs) sometime dominate the MRI findings, which include cortical, deep gray (70%) and leptomeningeal involvement (33%). Frequently, the lesions enhance and may be evident on diffusion weighted imaging (DWI). The BRAO are best evaluated with fluorescein angiography, which may show the pathognomonic multifocal fluorescence. Gass plaques are frequently present and reflect endothelial damage. Brain biopsy shows microinfarction to be the basic pathology, but more recent pathological studies have shown endothelial changes that are typical for an antiendothelial cell injury syndrome. Elevated levels of Factor VIII and von Willebrand Factor Antigen reflect the endothelial perturbation. Despite extensive evaluations, a procoagulant state has never been demonstrated. SS is an autoimmune endotheliopathy that requires treatment with immunosuppressants: steroids, cyclophosphamide, and intravenous immunoglobulin, usually in combination. Aspirin is a useful adjunct.

Case report: Hepatic arteriovenous fistula in a 3 month old Border Collie

A 3-month-old female Border Collie puppy presented with a 7-day history of vomiting, diarrhoea and neurological signs. The neurological signs started as vague disorientation and listlessness, but progressed to circling, ataxia, head pressing and profuse salivation. During the 48 hours prior to referral the puppy had four seizures; these had been well controlled with intravenous diazepam. Clinical examination revealed generalised weakness, lethargy and depression. The puppy was in poor body condition (body condition score 1/5), otherwise physical examination was unremarkable. Neurological examination revealed mild proprioceptive deficits in all four limbs, poor anal tone, neck weakness and a slight tremor. Ophthalmic examination revealed normal ocular structures, although vision was questionable, with slow pupillary light reflexes, poor following ability and absent menace responses (although the menace response is a learned response and may not be present in young animals). At this stage the generalised weakness and multifocal neurological signs were the most prominent problems and further investigations were performed.

The clinical course of acute disseminated encephalomyelitis

The objective of this review is to describe recent advances in understanding the clinical course of pediatric and adult acute disseminated encephalomyelitis (ADEM), especially the risk of relapse and conversion to multiple sclerosis (MS). The diagnosis of ADEM is reached on clinical grounds, typically in the setting of a post-infectious meningoencephalitic syndrome associated with multifocal neurological symptoms and signs, magnetic resonance imaging (MRI) evidence of white matter lesions and exclusion of other causes. Although typically monophasic, several case series demonstrate 'multiphasic' or 'recurrent' forms of ADEM with clinical relapses occurring within a short interval of disease onset. Furthermore, the estimated risk of developing MS is substantial for both children (0–33%) and adults (∼35%). Advances in neuroimaging have identified some MRI features that have predictive value for a relapsing course but they are not accurate enough for therapeutic decision-making; a diagnosis of monophasic ADEM should be made with caution in all cases, especially those presenting in adulthood. Research in ADEM and related disorders remains hampered by lack of prospective studies, specific and reproducible clinical case definitions and variable follow-up methods. Standardization of these variables would facilitate identification of more accurate diagnostic and prognostic variables, discovery and testing of potential objective biomarkers that would, in turn, allow early prediction of a relapsing course and appropriate therapeutic interventions.

Leptomeningeal infiltration as the presenting manifestation of a malignant glioma

Infiltration of the leptomeninges by a malignant glioma typically occurs with recurrent supratentorial tumors, but patients may present with leptomeningeal gliomatosis before the primary tumor is diagnosed. This report describes two patients who presented with headache and signs of multifocal neurological disease. One of the patients had neurofibromatosis type I. In both patients the cerebrospinal fluid examination showed a mild pleocytosis, but malignant cells were not detected. The diagnosis of leptomeningeal gliomatosis was not confirmed until autopsy, but in retrospect imaging showed a small, asymptomatic primary tumor in both patients. Leptomeningeal gliomatosis should be considered in the differential diagnosis of chronic meningitis, if the patient is afebrile and if there are multifocal neurological signs, even when a primary tumor is not obvious.

Acute disseminated encephalomyelitis following hepatitis A virus infection

Acute disseminated encephalomyelitis is an immune-mediated demyelinating disorder usually encountered in children or adolescents and characterized by multifocal neurologic deficits of rapid onset. It is often preceded by various infectious diseases or vaccination, but acute disseminated encephalomyelitis developing after hepatitis A virus infection is rare. We present such a case in a 9-year-old patient who illustrates the importance of considering acute disseminated encephalomyelitis in patients who develop multifocal neurologic signs after hepatitis A virus infection. We suggest that patients with acute disseminated encephalomyelitis be screened for hepatitis A virus because of the occurrence of asymptomatic hepatitis A virus infection.

CRMP‐5 neuronal autoantibody: Marker of lung cancer and thymoma‐related autoimmunity

We have defined a new paraneoplastic immunoglobulin G (IgG) autoantibody specific for CRMP-5, a previously unknown 62-kd neuronal cytoplasmic protein of the collapsin response-mediator family. CRMP-5 is in adult central and peripheral neurons, including synapses, and in small-cell lung carcinomas. Since 1993, our Clinical Neuroimmunology Laboratory has detected CRMP-5-IgG in 121 patients among approximately 68,000 whose sera were submitted for standardized immunofluorescence screening because a subacute neurological presentation was suspected to be paraneoplastic. This makes CRMP-5 autoantibody as frequent as PCA-1 (anti-Yo) autoantibody, second only to ANNA-1 (anti-Hu). Clinical information, obtained for 116 patients, revealed multifocal neurological signs. Most remarkable were the high frequencies of chorea (11%) and cranial neuropathy (17%, including 10% loss of olfaction/taste, 7% optic neuropathy). Other common signs were peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%), and neuromuscular junction disorders (12%). Spinal fluid was inflammatory in 86%, and CRMP-5-IgG in 37% equaled or significantly exceeded serum titers. Lung carcinoma (mostly limited small-cell) was found in 77% of patients; thymoma was in 6%. Half of those remaining had miscellaneous neoplasms; all but two were smokers. Serum IgG in all cases bound to recombinant CRMP-5 (predominantly N-terminal epitopes), but not to human CRMP-2 or CRMP-3. Ann Neurol 2001:49:146–154

CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity

We have defined a new paraneoplastic immunoglobulin G (IgG) autoantibody specific for CRMP-5, a previously unknown 62-kd neuronal cytoplasmic protein of the collapsin response-mediator family. CRMP-5 is in adult central and peripheral neurons, including synapses, and in small-cell lung carcinomas. Since 1993, our Clinical Neuroimmunology Laboratory has detected CRMP-5-IgG in 121 patients among approximately 68,000 whose sera were submitted for standardized immunofluorescence screening because a subacute neurological presentation was suspected to be paraneoplastic. This makes CRMP-5 autoantibody as frequent as PCA-1 (anti-Yo) autoantibody, second only to ANNA-1 (anti-Hu). Clinical information, obtained for 116 patients, revealed multifocal neurological signs. Most remarkable were the high frequencies of chorea (11%) and cranial neuropathy (17%, including 10% loss of olfaction/taste, 7% optic neuropathy). Other common signs were peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%), and neuromuscular junction disorders (12%). Spinal fluid was inflammatory in 86%, and CRMP-5-IgG in 37% equaled or significantly exceeded serum titers. Lung carcinoma (mostly limited small-cell) was found in 77% of patients; thymoma was in 6%. Half of those remaining had miscellaneous neoplasms; all but two were smokers. Serum IgG in all cases bound to recombinant CRMP-5 (predominantly N-terminal epitopes), but not to human CRMP-2 or CRMP-3.

Diagnostic criteria and clinical procedures in HIV-1 associated progressive multifocal leukoencephalopathy

The diagnosis of definite progressive multifocal leukoencephalopathy (PML) has been a neuropathological domain. We reviewed all Human Immunodeficiency Virus Type 1 (HIV-1) seropositive patients in our institution between 01.01.1989 and 31.12.1994 and identified 20 823 cases with PML by clinical and imaging criteria. Diagnosis was neuropathologically confirmed in 5 cases. Diagnostic criteria included rapid onset (<2 weeks) of multifocal neurological signs and symptoms, advanced immunosuppression and asymmetric uni- or multifocal white matter lesions without mass effect, contrast enhancement or cortical atrophy in magnetic resonance imaging (MRI). The overall incidence of PML was stable over the observation period (≅2.5%). The mean age at onset (41.7 years) was significantly lower compared to HIV-1 seronegative PML patients (peak in the sixth decade of life), male patients prevailed (100%). Mean survival (3.9 months) was extremely short. Human polyoma virus JC (JCV) polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) demonstrated a considerable rate of possible cerebral co-infection with HIV-1 and JCV as well as subclinical infection with JCV. Therefore demonstration of JCV deoxyribonucleic acid by PCR in the CSF alone is not sufficient for clinical PML diagnosis. We present diagnostic criteria on the basis of epidemiological, neuroradiological and CSF parameters that allow us to make the clinical diagnosis of PML. Although quick and safe, routine stereotactic brain biopsy is not necessary to confirm the diagnosis.

Multiphasic disseminated encephalomyelitis mimicking multiple sclerosis

We report a case of multiphasic disseminated encephalomyelitis (MDEM) following viral illness presenting as multiple sclerosis (MS) in a 7-year-old boy. The patient had two episodes of alternating hemiparesis and other neurologic symptoms following viral infection, which were separated by 3 years. Neuroimaging studies demonstrated multiple, discrete, small nodules and large globular lesions in the cerebral white matter, basal ganglia, brainstem and cerebellar areas. Based on typical appearance of magnetic resonance imaging (MRI) and clinical manifestations including systemic symptoms such as fever, nausea, vomiting, headache and seizures followed by consciousness disturbance and other multifocal neurologic signs, the diagnosis of MDEM rather than that of MS was made. Because it is difficult to differentiate between MDEM and MS on the basis of the clinical history, the cerebrospinal fluid examination and evoked potential studies, this report emphasizes that the MRI study of the brain may provide an important clue for the diagnosis.

Acute Febrile Cerebrovasculitis

In December 1985, a patient was seen with an illness that was clinically compatible with the recently described clinical syndrome of acute febrile cerebrovasculitis, including fever, headache, altered mentation, multifocal neurologic signs, and cerebrospinal fluid pleocytosis. An extensive medical evaluation failed to reveal a cause, until, retrospectively, she was shown to have antibodies to Rickettsia typhi. Detailed serologic analysis with enzyme immunoassays and protein immunoblots indicated that she was infected with a non-spotted fever group Rickettsia, most likely either R typhi or Rickettsia canada. Serum samples from a mouse trapped at her home contained antibody only to R canada. Evaluation of patients with acute febrile cerebrovasculitis in the future should include rickettsial blood cultures to attempt specific identification of the species involved.

Differential diagnosis of dementing diseases

Evaluation of the cognitively impaired patient necessitates documentation of dementia, with the help of standard and robust neuropsychological tests, followed by identification of focal, multifocal, or subcortical neurological signs which help differentiate the most common dementing diseases. The usual diagnostic dilemma is to distinguish Alzheimer’s disease from circulatory dementia. Until recently, Alzheimer’s disease was considered a diagnosis of exclusion, with confirmation only by pathological examination. Invasive tests, such as lumbar puncture for protein markers or skin biopsy for genetic markers, may aid in the antemortem diagnosis of Alzheimer’s. Noninvasively determined information which may provide diagnostic clues includes family history of dementia and fingerprint patterns. Circulatory dementia need not be confined to multi-infarct dementia, but may also include dementia accompanying cerebrovascular or cardiovascular disease. Features associated with circulatory dementia include remote history of urinary and gait disturbances, ear hair growth, and “infarcts” on MRI and CTT. Although the significance of “infarcts” on MRI is unclear, they are associated with high Hachinski ischemic score, hypertension, and cardiac arrhythmias. “Infarcts” on MRI are more sensitive, but less specific, than “infarcts” on CTT, in diagnosing circulatory dementia. Techniques of decision analysis can help determine the diagnostic utility of the Hachinski score and its components, as well as of imaging techniques and other diagnostic aids, in differential diagnosis. In drug trials for Alzheimer’s, where maximum sensitivity in the diagnosis of circulatory dementia is needed to exclude inappropriate subjects, the MRI is the imaging procedure of choice. Conversely, drug trials for circulatory dementia should use the CTT to enhance specificity. In the absence of specific therapeutic intervention, either procedure may be used, as overall diagnostic utility of the CTT and MRI, as determined by the Brier score, is comparable.

Canine fucosidosis: clinical findings

ABSTRACTThe clinical course of canine fucosidosis, a neurovisceral lysosomal storage disease, is described from observations of 31 affected English Springer Spaniels. The diagnosis of fucosidosis was suggested by the development of multifocal neurological signs in the second year of life and confirmed by a deficiency of alpha‐L‐fucosidase activity in plasma and leucocytes. The progressive motor and mental deterioration was similar in all dogs and no affected animal survived to four years of age. Alpha‐L‐fucosidase activity in plasma was &lt;0·05 μ/1 in all cases. The activity in leucocytes and other tissues was &lt; 5 per cent of that of normal dogs.Vacuolated leucocytes occurred in cerebrospinal fluid, blood and bone marrow. The enlargement of peripheral nerves which is observed at autopsy could be detected by palpation of the ulnar nerve in advanced disease, however the results of electrodiagnostic studies were within normal limits.The clinical signs and pathological changes were found to be remarkably consistent from case to case making it an excellent model for investigating therapeutic strategies in human lysosomal storage disorders.

Acute Febrile Cerebrovasculitis: A Syndrome of Unknown, Perhaps Rickettsial, Cause

In late 1983, five patients living near Charlottesville, Virginia, were treated for an unusual syndrome of fever, headache, altered mentation, multifocal neurologic signs, and cerebrospinal fluid pleocytosis. Clinical signs of brainstem disease developed in four patients. All five had had recent exposure to forests or wood and contact with flea-infested dogs. Two patients died; one survivor has had recurrent seizures. Brain biopsy samples in two patients and autopsy findings in another showed cerebral vasculitis and perivasculitis involving mostly venules and capillaries. In the autopsy, the severest vascular lesions involved the brainstem and thalami, where they were accompanied by acute fibrinoid necrosis, but discrete vascular lesions of lesser intensity were randomly distributed in the white matter and cortex. Serologic studies on paired specimens in four patients showed significant cross-reacting antibody responses to rickettsial (typhus-group) antigens in the indirect hemagglutination, latex agglutination, and IgM microimmunofluorescence tests, but no agent was visualized or isolated. The cause of this serious inflammatory disorder is unknown.

Herpes Simplex and Neurologic Deficits

To the Editor.— In his discussion of recurrent herpes simplex of the skin in the QUESTIONS AND ANSWERS section (237:579, 1977), Friedman states that "no objective neurological deficits, sensory or motor, have been noted." This is incorrect. While such deficits are rare with recurrent herpes simplex, they have been noted. For example, Von Hoff et al 1 reported a patient with multifocal sensory and motor neurological signs associated with recurrent labial herpes simplex. Similarly, Lewis and Morris 2 described a patient with recurrent herpes simplex associated with Bell's palsy.

Neurological manifestations of infective endocarditis: a review.

Neurological complications are seen in patients with bacterial endocarditis and their incidence has not changed with the advent of antibiotics. Patients with abnormal neurological signs have a grave prognosis. Neurological sequelae of bacterial endocarditis are most often due to septic embolization producing ischemia and/or suppuration, resulting in infarction, hemorrhage, meningoencephalitis, or abscess. Clinical findings vary with the portion of the nervous system affected. The diagnosis should be suspected in the febrile patient with neurological signs of acute onset, the young patient with hemiplegia, the older patient with sudden changes in mentation, or the patient of any age with multifocal neurological signs. Diagnostic measures should include a careful history and physical examination, blood cultures and lumbar puncture where not contraindicated. Treatment is based on therapy of the bacterial endocarditis with bactericidal drugs, and therapy of intracerebral lesions with drugs that penetrate the blood-brain barrier. Consideration should be given to surgical intervention in mycotic aneurysms and brain abscesses.