Prominent Neurological Symptoms Research Articles

POLG-Related Ataxia and Ophthalmoplegia: A Case Report (P9-11.008)

<h3>Objective:</h3> Not applicable <h3>Background:</h3> Genetic variants of the POLG gene result in mitochondrial DNA defects and account for a large proportion of mitochondrial diseases. These disorders encompass a spectrum of phenotypes, with onset ranging from infancy to late adulthood. In addition to hepatic dysfunction and myopathy in younger populations, and hormone derangements with cataracts in older patients, patients may also present with prominent neurologic symptoms, including ataxia, parkinsonism, epilepsy, and ophthalmoplegia. More than 300 pathogenic mutations of POLG have been reported and there are no clear genotype-phenotype correlations. Given the rarity of these syndromes and wide range of clinical phenotypes, there is often delay in diagnosis. <h3>Design/Methods:</h3> Not applicable <h3>Results:</h3> We present a 47-year old woman with symptoms of difficulty speaking and development of tremor, vision loss, dizziness, and gait difficulty progressing over several months. Initial exam was significant for ataxia and choreiform movements. Extraocular movement (EOM) testing revealed delayed initiation of saccades and slow, saccadic pursuits with nystagmus. Bloodwork, which included extensive workup for causes of chorea and ataxia, electromyography/nerve conduction studies, and imaging (MRI brain and malignancy work-up) were unremarkable. She continued to decline with development of ophthalmoplegia, ptosis, numbness, weakness, and pain, severely limiting her functional capacity. Whole exome sequencing was performed and showed a heterozygous variant of uncertain significance (VUS) in the POLG gene, which may explain her presentation. <h3>Conclusions:</h3> This case adds to a growing collection of case reports describing the various phenotypes of POLG-related disorders. Early detection of POLG variants and phenotype/genotype characterization may help guide development of future treatments for patients with similar conditions. <b>Disclosure:</b> Dr. Peabody has nothing to disclose. An immediate family member of Dr. Shpiner has received personal compensation for serving as an employee of University of Miami.

Neurogenic rosacea in Korea.

Rosacea with severe neurological symptoms such as burning and stinging is often not treated effectively by conventional therapies. The aim of this study was to investigate the clinical characteristics of Korean rosacea patients with prominent neurological symptoms. The demographic features, medical history, clinical manifestations and treatment modalities of 17 neurogenic rosacea patients who had prominent neurological symptoms and 106 erythematotelangiectatic rosacea (ETR) patients as a control group were investigated. All 17 neurogenic rosacea patients had severe persistent erythema with burning/stinging sensation limited to both cheeks. Among these patients, 94.1% were female (16/17). Heat stimuli (58.8%, 10/17) and stress (52.9%, 9/17) were major aggravating factors. Fourteen of 17 patients (82.3%) improved after receiving anticonvulsants and antidepressants. In conclusion, rosacea patients with severe neurological symptoms show distinct clinical manifestations and should be classified separately, and a different therapeutic approach is necessary for them.

Transient blindness associated with mild encephalitis/encephalopathy with a reversible splenial lesion (MERS): a case report and review of literature

BackgroundMild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinical-radiological syndrome that can be related to infectious and non-infectious conditions. The most prominent neurological symptoms are disturbance of consciousness, abnormal speech, delirious behavior, seizures, muscle weakness, ophthalmoplegia, facial nerve paralysis and headache. Here we report the case of a child with MERS presenting with the unusual symptom of bilateral transient blindness.Case presentationA 4-year-old female patient, with a history of fever, abdominal pain, loss of appetite and cough lasted for a few days, experienced 3 episodes of transient bilateral loss of vision with difficulty in walking. Her physical examination showed absence of focal neurological and meningeal irritation signs, although responsiveness was slightly impaired. The ophthalmologic evaluation, including a fundus oculi examination, was negative.The electroencephalogram showed slow activity in the temporo-occipital regions, more evident in the right hemisphere. A lumbar puncture was performed and cerebrospinal fluid analysis revealed normal glycorrhachia, cell counts, protein levels and IgG index.Magnetic resonance imaging of the brain showed a signal alteration in the splenium of the corpus callosum, without contrast enhancement. This finding was suggestive of a reversible cytotoxic lesion. Empiric antiviral treatment with acyclovir and intravenous dexamethasone was initiated. Polymerase chain reaction search for neurotropic viral nucleic acid sequences in the cerebrospinal fluid was negative, while a low number of HHV-6 DNA copies was detected in the blood.Electroencephalograms were repeated in the following days, showing a progressive normalization of the pattern. The child was discharged without symptoms after 10 days of treatment with oral corticosteroids. After 40 days, brain magnetic resonance imaging showed a complete normalization of the signal alteration in the splenium of the corpus callosum.ConclusionTransient blindness was reported as an initial symptom of MERS in a few children. To date, there is no evidence of effective treatment methods. Nonetheless, MERS diagnosis provides pediatricians with valuable prognostic information in order to reassure patients and their families about the good outcome of this disease.

The Most Common Treatable Neurometabolic Epilepsies in Children

Epilepsy is a common neurological disorder in childhood with prominent neurological manifestations, signs, and symptoms in inherited neurometabolic disorders. Accurate diagnosis of neurometabolic disorders in epileptic patients increases the possibility of a specific treatment to improve epilepsy. Therefore, early diagnosis is essential in potentially treatable epileptic disorders. Various seizure types occur in neurometabolic disorders, which are often refractory to antiepileptic drugs (without the treatment of the underlying neurometabolic disorders). Patients with underlying disorders have severe clinical presentations, such as refractory seizures. In addition, they do not respond to antiepileptic drugs in many cases. In the epileptic patients with developmental delay and/or regression, neurometabolic disorders should be considered in the presence of abnormal neurological examination and brain imaging with specific patterns. Some of these disorders are potentially treatable. Therefore, neurologists should determine the etiology of epilepsy, especially in pediatric patients, and the treatment should not be restricted to symptomatic therapy. The present study aimed to introduce some of the treatable causes of epilepsy in pediatric patients.

Remodel mitochondria and get energized

Patients with mitochondrial disease often present with prominent neurologic symptoms. Common features include encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Because skeletal muscle is the tissue with the highest metabolism in the body, with a staggering 50-fold increase in oxygen consumption from rest to maximal exercise, myopathic symptoms in mitochondrial disease are probably the most common presentation of the conditions. Myopathic symptoms can present as limb weakness, bulbar weakness with dysphagia, ptosis, external ophthalmoplegia, and exercise intolerance. Exercise intolerance is usually severe and, unlike most other neuromuscular conditions, typically does not relate to muscle weakness and wasting but to compromised generation of energy through oxidative phosphorylation. Thus, work capacity is often limited to a third of that in healthy persons,1,2 which prevents patients from participating in sport activities and performing activities of daily living such as climbing stairs, grocery shopping, jogging, and playing with children.

Pediatric NMDAR encephalitis: A single center observation study with a closer look at movement disorders.

Anti-N-Methyl-d-aspartate-receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in pediatric age. This retrospective observational study was aimed at describing the clinical characteristics of the disease in a cohort of children and teenagers. Eighteen patients (10 females and 8 males), with a median age of 12.4years at symptom onset were enrolled. The clinical presentation of the disease was marked by neurological manifestations in 13 patients and by severe psychiatric and behavioral symptoms in 5. The symptoms at onset varied according to the age: all the children presented with prominent neurological symptoms, whereas psychiatric symptoms were prominent in teenagers. Regardless the age, movement disorders (MDs) were distinctive symptoms during the acute stage of the disease. Several MDs might coexist in a given patient, and persist during sleep. The complexity, and the oddness of MDs often challenged their definition and the differential diagnosis with psychiatric manifestations and epileptic seizures. Stereotyped motor phenomena were the most typical MDs, and were recorded in all patients. Among them, perseveration, reproduction of acquired complex motor activities, and orofacial dyskinesia were the most distinctive features. In children, hyperkinetic MDs dominate; in teenagers, by contrast, a constellation of symptoms consistent with catatonia was the most frequent syndrome observed. The management of the several symptoms requires their accurate recognition, definition and assessment, and the knowledge of the potential side effects of antiepileptic and psychotropic drugs which could either mimic or worsen symptoms of encephalitis.

Metabolites-Mitochondria-Microglia (Mmma): Therapeutic Stategy for Treatment of Neural Inflammation and Neurodegeneration

Patients with mitochondrial disease often present with prominent neurologic symptoms; the alteration of mitochondrial metabolism produces an excess of ROS and cytokines that appeared implicated in the activation of microglia; similar considerations apply to Amyotrophic Latera Sclerosis (ALS) and other neurodegenerative disorders. The microglia polarization by mitochondrial metabolism modulation could be considered an option to treat the neuroinflammation and neurodegenerative disorders, similar to macrophage action in case of muscle inflammation and atrophy. Furthermore, thanks to the availability of several biomarkers including mitochondrial microRNAs it should be possible to monitor metabolic state and microglia mitochondrial metabolic shift.

Analysis of Brain Mitochondria Using Serial Block-Face Scanning Electron Microscopy.

Human brain is a high energy consuming organ that mainly relies on glucose as a fuel source. Glucose is catabolized by brain mitochondria via glycolysis, tri-carboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathways to produce cellular energy in the form of adenosine triphosphate (ATP). Impairment of mitochondrial ATP production causes mitochondrial disorders, which present clinically with prominent neurological and myopathic symptoms. Mitochondrial defects are also present in neurodevelopmental disorders (e.g. autism spectrum disorder) and neurodegenerative disorders (e.g. amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases). Thus, there is an increased interest in the field for performing 3D analysis of mitochondrial morphology, structure and distribution under both healthy and disease states. The brain mitochondrial morphology is extremely diverse, with some mitochondria especially those in the synaptic region being in the range of <200 nm diameter, which is below the resolution limit of traditional light microscopy. Expressing a mitochondrially-targeted green fluorescent protein (GFP) in the brain significantly enhances the organellar detection by confocal microscopy. However, it does not overcome the constraints on the sensitivity of detection of relatively small sized mitochondria without oversaturating the images of large sized mitochondria. While serial transmission electron microscopy has been successfully used to characterize mitochondria at the neuronal synapse, this technique is extremely time-consuming especially when comparing multiple samples. The serial block-face scanning electron microscopy (SBFSEM) technique involves an automated process of sectioning, imaging blocks of tissue and data acquisition. Here, we provide a protocol to perform SBFSEM of a defined region from rodent brain to rapidly reconstruct and visualize mitochondrial morphology. This technique could also be used to provide accurate information on mitochondrial number, volume, size and distribution in a defined brain region. Since the obtained image resolution is high (typically under 10 nm) any gross mitochondrial morphological defects may also be detected.

Clinical and MRI evaluation of anxiety as the first symptom of sporadic Creutzfeldt-Jakob disease: A case report.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, transmissible prion disease of the brain, characterized by prominent neurological symptoms and progressive dementia. Early psychiatric manifestations as an initial or sole symptom of sCJD are relatively rare. The current report describes an elderly female patient with sCJD demonstrating anxiety as an initial symptom. The present patient was initially diagnosed with adjustment disorder and anxiety; however, the rapid deterioration of the patient's cognitive and neurological functioning led to a diagnosis of sCJD. Diffusion-weighted magnetic resonance images of the brain supported a diagnosis of sCJD, and it was posited that the abnormalities of gray matter that were observed within the bilateral cingulate cortex may be the pathophysiological basis of the anxiety associated with this case of sCJD. The patient eventually succumbed to inhalational bronchopneumonia 5 months after anxiety onset. The present case report emphasizes the importance of secondary causes of anxiety symptoms in elderly patients, and indicates that brain DWI is a non-invasive and useful examination in the early diagnosis of sCJD.

7-Dehydrocholesterol Modifies the Operation of Kv1.3 Channels in T Cells Isolated from Smith-Lemli-Opitz Syndrome Patients

In vitro manipulation of membrane sterol level has an impact on the regulation of ion channels, however, a comprehensive study is lacking to confirm the physiological or pathophysiological significance of these experiment. Smith-Lemli-Opitz syndrome (SLOS) is characterized by a reduced or abolished activity of 7-dehydrocholesterol (7DHC) reductase, which leads to the elevation of the 7DHC in the tissues and blood. We utilized T cells isolated from SLOS patients to address the question if in vivo altered membrane sterol composition impairs the operation of Kv1.3, the predominant voltage-gated ion channel of T cells, and if altered Kv1.3 function is reflected in impaired mitogenic responses of SLOS T lymphocytes.Using whole-cell patch-clamp technique we showed that the activation kinetics of Kv1.3 is slower and the midpoint of the voltage-dependence of steady-state activation is shifted to depolarized potentials in SLOS T cells as compared to age-matched controls. Similar changes in the kinetic and equilibrium parameters of Kv1.3 gating were detected in control T cells loaded with 7DHC using 7DHC/cyclodextrin complex. Upon removal of putative sterol binding sites of Kv1.3 the channel become insensitive to 7DHC loading. Functional assays revealed that modified operation of Kv1.3 in the SLOS T cells is associated with impaired proliferation rate (CFSE method) and a defect in the early steps of Kv1.3¬- and Ca2+-dependent activation process (CD154/CD40L expression) in CD3+ cells.Our conclusion is that the function of Kv1.3 is modified in SLOS via a direct coupling to the 7DHC in the cell membrane. We propose that this ion channel-sterol interaction reveals a molecular mechanism that may contribute to the pathophysiological conditions in SLOS and lead to the most prominent neurological and cardiovascular symptoms via influencing the physiological function of ion channels.

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.

Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.

Allgrove syndrome: an Egyptian family with two affected siblings

BackgroundAllgrove or AAA (Triple A) syndrome is a rare autosomal recessive disease characterized by achalasia, alacrima, adrenocorticotrophic insufficiency and some neurologic abnormalities. Case reportHere we report two brothers 13 and 15years old, with variable features of the syndrome, with prominent neurological symptoms which started in the first decade and, led to motor paralysis and severe muscle wasting in the elderly brother in the second decade of life. Moderate achalasia developed at 9years in the older brother and showed a slowly progressive course with development of chest pain and dysphagia. Alacrima was not evident before the age of 12years.The neurological symptoms were less severe in the younger brother. He suffered alacrima that started at age of 11years and mild dysphagia due to achalasia at age of 12years, both being slowly progressive.This paper highlights early features of this syndrome among Egyptian population and the importance to exclude Allgrove syndrome in the presence of progressive neurological dysfunction. To concludeAllgrove syndrome should be suspected in patients with neurological impairment associated with any of the main symptoms of the syndrome (alacrima, achalasia and adrenal insufficiency).

Clinical characterization of a presenilin 1 mutation (F177S) in a family with very early-onset Alzheimer's disease in the third decade of life

BackgroundEarly-onset familial Alzheimer disease (AD) is an autosomal dominant disorder caused by mutations in the amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 gene. The objective of this study was to characterize the phenotype in a large family with a PSEN1 F177S mutation by performing detailed clinical assessments, neuroimaging, and neuropathological analysis. MethodsIn two subjects, clinical and neuropsychological assessments, structural magnetic resonance imaging, F-18-2-fluoro-2-deoxy-D-glucose positron emission tomographic imaging, AD biomarkers in cerebrospinal fluid and genetic analysis were available. In three deceased affected subjects, medical records were reviewed. In one subject, a complete neuropathological examination was available. ResultsCognitive impairment and neurological symptoms developed homogeneously around 30 years of age and worsened rapidly. All subjects died about 7 years (range, 6–8 years) after disease onset before 40 years of age. All technical diagnostic information (neuroimaging, cerebrospinal fluid) were typically for AD. Neuropathology showed abundant neuritic plaques and neurofibrillary tangles, typical of severe AD. Antidementia treatment in one subject did not alter the length of survival. ConclusionsThe PSEN1 F177S mutation leads to typical AD starting at age 30 and a homogeneous phenotype with rapid cognitive decline and prominent neurological symptoms. Excessive amyloid beta 42 production in the brain cortex corresponds well with other PSEN1 mutations.

Neurogenic Rosacea: A Distinct Clinical Subtype Requiring a Modified Approach to Treatment

Rosacea is generally categorized into 4 distinct clinical subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular.1 Granulomatous rosacea, rosacea fulminans, and perioral dermatitis have been described as additional variants.2 Herein we describe 14 patients with rosacea and prominent neurologic symptoms, who represent another distinct subset of rosacea meriting a unique approach to management.

Psychiatric Manifestations of Creutzfeldt-Jakob Disease: A 25-Year Analysis

This study characterizes the type and timing of psychiatric manifestations in sporadic Creutzfeldt-Jakob disease (sCJD). Historically, sCJD has been characterized by prominent neurological symptoms, while the variant form (vCJD) is described as primarily psychiatric in presentation and course: A retrospective review of 126 sCJD patients evaluated at the Mayo Clinic from 1976–2001 was conducted. Cases were reviewed for symptoms of depression, anxiety, psychosis, behavior dyscontrol, sleep disturbances, and neurological signs during the disease course. Eighty percent of the cases demonstrated psychiatric symptoms within the first 100 days of illness, with 26% occurring at presentation. The most commonly reported symptoms in this population included sleep disturbances, psychotic symptoms, and depression. Psychiatric manifestations are an early and prominent feature of sporadic CJD, often occurring prior to formal diagnosis.

Psychiatric Manifestations of Creutzfeldt-Jakob Disease: A 25-Year Analysis

This study characterizes the type and timing of psychiatric manifestations in sporadic Creutzfeldt-Jakob disease (sCJD). Historically, sCJD has been characterized by prominent neurological symptoms, while the variant form (vCJD) is described as primarily psychiatric in presentation and course: A retrospective review of 126 sCJD patients evaluated at the Mayo Clinic from 1976-2001 was conducted. Cases were reviewed for symptoms of depression, anxiety, psychosis, behavior dyscontrol, sleep disturbances, and neurological signs during the disease course. Eighty percent of the cases demonstrated psychiatric symptoms within the first 100 days of illness, with 26% occurring at presentation. The most commonly reported symptoms in this population included sleep disturbances, psychotic symptoms, and depression. Psychiatric manifestations are an early and prominent feature of sporadic CJD, often occurring prior to formal diagnosis.

Uncommon causes of dementia: rare, but not marginal

Dementia is one of the most frequent and disabling health problems of our times. During the past twenty years, we have witnessed growing public and professional interest in dementia, its diagnosis and causes. This has led to the introduction of better methods of detection of cognitive impairment, coupled with early diagnosis of Alzheimer's disease and, to a lesser degree, of other forms of dementia. However, if the clinical presentation of patients does not follow the typical pattern of progressive memory loss starting in later life, then currently available diagnostic methods are less likely to be useful and patients with dementia may go unidentified for prolonged periods of time. Some of the less frequent causes of dementia may initially present with psychological or behavioral disturbances, others are associated with prominent neurological signs and symptoms. Patients may also present with marked deficits in cognitive domains other than memory, such as impaired language, which makes the diagnostic workup more difficult and onerous.

Noninvasive Cerebrovascular Assessment of Takayasu Arteritis

Despite prominent neurological symptoms reported in Takayasu arteritis (TA), a complete evaluation of the cerebral circulation has not been consistently performed. The purpose of this study is to describe MR angiography (MRA), color Doppler flow imaging, and transcranial Doppler (TCD) findings in the extracranial and intracranial cerebral arteries in TA. MRA, color Doppler flow imaging, and TCD were performed in 21 patients with TA. Intima-media thickness was measured in the common carotid artery. The correlation between noninvasive studies and panaorto-arteriography was examined for supraortic vessels. Cerebral angiography findings were compared with the noninvasive methods in 7 patients. Intracranial hemodynamic changes detected by TCD were compared with extracranial circulation lesions assessed by panaorto-arteriography. Noninvasive vascular techniques showed at least 1 abnormality in the extracranial and/or intracranial cerebral arteries in 20 of 21 patients (95%). Both MRA and color Doppler flow imaging showed a substantial correlation in the ability to detect obstructive lesions in supra-aortic vessels compared with panaorto-arteriography. High-resolution ultrasonography displayed common carotid artery wall thickening in 5 vessels that were considered normal by arteriography. In 24% of patients, MRA and TCD showed abnormalities consistent with stenosis of the basal cerebral arteries. In 10 patients with severe extracranial circulation involvement (detected by arteriography), TCD displayed intracranial hemodynamic changes consisting of dampened or blunted waveforms with low pulsatility. The comprehensive assessment of cerebral circulation in TA patients by noninvasive methods allowed the detection of a high rate of diverse vascular abnormalities in both extracranial and intracranial circulation.

Cerebellar pathology in sporadic and familial Alzheimer's disease including APP 717 (Val→Ile) mutation cases: A morphometric investigation

Familial Alzheimer's disease (FAD) tends to present with more prominent neurological symptoms including cerebellar signs than sporadic Alzheimer's disease (SAD). In order to elucidate the pathological differences in the cerebellum, which may be associated with the cerebellar symptoms, we have investigated morphometrically β-amyloid deposits, atrocytosis, Purkinje cells and dentate neurons in the cerebellum of 10 FAD patients including two cases with the β-amyloid precursor protein (APP) gene mutation (APP717 Val→Ile), 10 SAD patients and 10 non-demented age-matched controls. The regions examined included the molecular, Purkinje cell and granular cell layers, the cerebellar white matter and the dentate nucleus. Purkinje cell density in FAD was significantly lower than in SAD. There were no significant differences in the density of dentate neurons among the three groups. The density of astrocytes in FAD was significantly greater than that in SAD in the granular cell and Purkinje cell layers and in the white matter. There were no significant differences in the amount and subtypes of β-amyloid deposits (extracellular, vascular and perivascular) between FAD and SAD in all the regions investigated. In two cases with the APP mutation, both Purkinje cell loss and β-amyloid deposition in the cerebellum were greater than the mean for FAD and SAD cases. Astrocytosis in the mutation cases was not greater than the mean for FAD cases except for the dentate nucleus in one case. Extracellular β-amyloid deposits were not seen in any of the control cases although amyloid angiopathy was observed in one case. This study demonstrates for the first time that Purkinje cell loss and reactive astrocytosis of the cerebellum in FAD are more severe than in SAD, but that β-amyloid deposition in the cerebellum in both FAD and SAD are similar. The more prominent neurological signs observed in FAD may be explained by more severe neurodegeneration than are found in sporadic cases.

Whipple disease. Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Société Nationale Française de Médecine Interne.

Whipple disease is a rare, multiorgan disease with prominent intestinal manifestations. We report a retrospective clinical study of 52 patients recruited in various parts of France from 1967 to 1994. Seventy-three percent of the patients were male. Clinical manifestations preceding the diagnosis were articular for 35 patients (67%), digestive for 8 patients (15%), general for 7 patients (14%), and neurologic for 2 patients (4%). At a later stage of the disease, 44 patients (85%) presented diarrhea, weight loss, and malabsorption, while 8 patients (15%) did not show any gastrointestinal symptom throughout the development of the disease. Forty-three patients (83%) presented arthralgia or arthritis, and 11 (21%) had prominent neurologic symptoms. In addition, cardiovascular symptoms were present in 9 patients (17%); mucocutaneous symptoms, in 9 patients (17%); pleuropulmonary symptoms, in 7 patients (13%); and ophthalmologic symptoms, in 5 patients (10%). All patients but 1 were given a positive diagnosis on histopathologic criteria: jejunal biopsy for 46 patients (90%), lymph node biopsy for 3 patients (6%), brain biopsy for 1 patient (2%), postmortem jejunal and cerebral biopsy for 1 patient (2%). With treatment, the disease evolved favorably in 47 patients (90%), while 5 patients (10%) had unfavorable outcomes (2 deaths from neurologic involvement, 1 patient with chronic dementia, and 2 patients with digestive symptoms insensitive to antimicrobial therapy). Of the 41 patients initially treated successfully and whose treatment has been completed, clinical evolution after discontinuation of treatment was favorable in 34 cases (83%). Clinical relapses occurred in 7 patients. No relapse was observed after treatment by trimethoprim-sulfamethoxazole, alone or following a combination of penicillin and streptomycin, or after the combination of penicillin and streptomycin, whatever the oral follow-up treatment prescribed. The evolution of patients showing a relapse was favorable in all cases after reintroduction of antibiotic therapy. These results are discussed in the light of previously published series and case reports of Whipple disease. The diagnosis of the disease remains difficult at an early phase or when digestive symptoms are absent. It is noteworthy that proximal enteroscopy is sometimes misleading, considered normal on macroscopic examination and nonspecific on pathologic grounds. A normal erythrocyte sedimentation rate represents another pitfall. Histopathology is the key for positive and differential diagnosis, and may require multiple and repeated biopsies. Findings from molecular biology confirm the central role of an uncultured Gram-positive bacillus which was named in 1992 Tropheryma whippelii. A recent report suggests that polymerase chain reaction (PCR) analysis of peripheral blood might allow the diagnosis of Whipple disease in some cases. However, immunologic or cellular parameters such as macrophagic function may play an important, although not clearly elucidated, role in the pathogeny of the disease. Trimethoprim-sulfamethoxazole should be considered the antimicrobial agent of choice in the treatment of Whipple disease, minimizing the risk of cerebral involvement and relapses.