Isolated CNS Sarcoidosis Versus Systemic Sarcoidosis With CNS Involvement: A Same Disease?

Neurological involvement occurs in 5 to 15% of patients with sarcoidosis. It rarely represents the sole manifestation of the disease, a condition called isolated neurosarcoidosis. Objectives: To describe patients with definite isolated central neurosarcoidosis. To compare their characteristics to a group of systemic sarcoidosis with central neurologic involvement. Methods: Monocentric retrospective study of all patients presenting with central neurosarcoidosis (NS) over a 10 year period, subsequently divided into 2 groups: isolated neurosarcoidosis (INS) and systemic neurosarcoidosis (SNS). Results: We report 10 cases of INS and subsequently, we compared their characteristics to a group of 30 patients with SNS. INS patients exhibited brain parenchymal involvement (8/10), meningeal disease (8/10), myelitis (3/10), cranial neuropathy (3/10), neuroendocrine impairment (1/10). Cerebro-spinal fluid (CSF) analysis was conducted in 8/10 patients and showed pleocytosis in 6/8 (75%), elevated protein level in (4/8) 50%, oligoclonal intrathecal synthesis in 1/5 (20%). All patients received steroids, 7/10 (70%) required associated immunosuppressive therapy, 5 of which TNFα inhibitors. When compared to patients with SNS, INS patients were more likely to experience seizures (60% vs 23.3%); display encephalic parenchymal enhancing lesions (80% vs 39.3%) or encephalic leptomeningeal involvement (80% vs 35.7%). Serum angiotensin converting enzyme (ACE) was elevated in a third of patients with SNS but none of those with INS. Conclusion: The phenotypes of patients with INS are similar to the ones described in SNS. Serum ACE should not be regarded as a diagnostic test in patients with isolated neurosarcoidosis but could be useful in detecting subclinical extra neurologic involvement during follow up.

TWINKLE gene mutation: report of a French family with an autosomal dominant progressive external ophthalmoplegia and literature review.

BACKGROUND: Multiple mitochondrial DNA (mtDNA) deletions usually have a mendelian inheritance secondary to mutation in nuclear genes. One of these is the Twinkle gene whose mutation is responsible for autosomal dominant progressive external ophthalmoplegia (PEO). The number of reported cases with mainly myopathic symptoms and possible nervous system involvement related to Twinkle gene mutation is limited. We present a new French family of whom two members displayed myopathy and neuropathy associated with PEO, and we perform a clinical review in light of other observations reported in the literature. METHODS: The proband, one son and the daughter have been investigated. Southern blot analysis and long-range PCR assay have been performed from muscle biopsy specimens. Coding exons and flanking intron regions of polymerase gamma (POLG) and DNA helicase (Twinkle) genes were sequenced. RESULTS: Multiple mitochondrial DNA deletions have been found and sequencing of the Twinkle gene showed the change p.R374Q. CONCLUSION: Two other families from the literature also had the R374Q mutation. Symptoms reported in association with this mutation were myopathy, peripheral neuropathy, dysarthria and/or dysphagia, respiratory insufficiency and parkinsonism. Respiratory insufficiency caused by chest wall weakness was reported in other families with different Twinkle gene mutations, and one might provide exercise intolerance, dysarthria and/or dysphagia as symptoms in favor of the diagnosis. Occurrence of impressive emaciation was a peculiarity in our family.

[Mutism and acute behavioral disorders revealing MELAS syndrome]. / Mutisme et troubles du comportement aigus révélant un syndrome MELAS.

INTRODUCTION: MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a rare genetic mitochondrial disease which can cause cerebral (cerebrovascular accident, migraine, mental deterioration..), sensorial (bilateral symmetrical deafness) and peripheral (muscular involvement, neuropathy) disorders potentially associated with diabetes, renal or cardiac disorders, or growth retardation. Eighty percent of the patients have the 3243 A>G mutation in the leucine RNA transfer gene. Clinical manifestations leading to discovery of the mutation can be extremely varied, affecting patients of different age groups. CLINICAL CASE: We report the case of a 49-year-old man who presented acute fits of confusion followed by mutism and praxic disorders. History taking revealed recently diagnosed type 2 diabetes, axonal neuropathy, and bilateral symmetrical deafness requiring hearing aids. The initial MRI showed FLAIR sequences with bi-parietal abnormalities, no signs of recent stroke on the DW/B10000 sequences, and basal ganglia calcifications. Blood tests and morphological findings ruled out a vascular origin. Search for lactic acidosis remained constantly negative in blood samples despite positive cerebrospinal fluid samples (N×3). The 3243 A>G mitochondrial DNA mutation was identified. The neuropsychological evaluation revealed a serious dysexecutive syndrome with a major impact on the patient's self sufficiency. CONCLUSION: Neurocognitive disorders are not common in MELAS syndrome. Brain MRI results and the presence of extra-neurological signs can be helpful for diagnosis.

[Diagnostic procedure of limb girdle muscular dystrophies 2A or calpainopathies: French cohort from a neuromuscular center (Bordeaux)]. / Diagnostic des dystrophies musculaires progressives des ceintures de type 2A ou calpaïnopathies : étude des patients du centre de référence des maladies neuromusculaires de Bordeaux (France).

BACKGROUND: Limb girdle muscular dystrophies are rare genetic diseases. Despite constant progress in genetics and biochemistry, the pathogenic mechanisms are not completely understood. Calpainopathy (LGMD2A) has been reported to be the most frequent autosomal recessive form of muscular dystrophy in several populations. Point mutations in CAPN3 are difficult to identify and the analysis is long and costly. The use of western blot does not seem to provide the expected sensitivity and specificity. PATIENTS AND METHOD: We studied all the patients diagnosed in the neuromuscular center of Bordeaux (France) with confirmed calpainopathy in order to establish the appropriate diagnostic approach (inclusion criteria: muscular biopsy with calpain 3 western blot study, two mutations in CAPN3). Patients with highly suspected calpainopathy (same criteria with only one mutation) were also analyzed. RESULTS: Our 13 patients belonged to 10 different families. Four patients had a normal western blot for calpain (WBn). We found high phenotypic variability with frequent atypical signs. The WBn group had less severe disease (a statistically significant later age of onset, a tendency toward lower CK levels and a slower disease course). We extended this comparison to the single mutation patients and we found the same results. CONCLUSION: Considering the lack of sensitivity of western blot protein analysis in LGMD2A, a normal western blot for calpain should not halt the genetic analysis. The western blot result seems to have prognostic value. A normal western blot may help genetic testing by highlighting some mutational hot spots in the CAPN3 gene.

Ontogeny of the striatal neurons expressing neuropeptide genes in the human fetus and neonate.

The distribution patterns of neurons expressing mRNAs for four neuropeptides in the human striatum were studied during ontogeny by the use of in situ hybridization. The results of our study demonstrate that somatostatin, enkephalin, dynorphin, and substance P mRNAs are present in striatal neuronal populations from week 12 of fetal life. Each neuronal population undergoes a specific differentiation. Neurons containing somatostatin mRNA are scattered throughout the caudate-putamen up until birth. Neurons containing enkephalin, dynorphin, or substance P mRNAs evolve throughout fetal life in relation to caudate-putamen and patch-matrix compartmentalization. Neurons containing enkephalin mRNA (distinct from those containing substance P or dynorphin mRNAs) are present in the matrix from week 12 of fetal life. These neurons are preferentially distributed in the matrix and, at birth, display higher enkephalin mRNA content in the matrix than in the patches. Dynorphin mRNA is found in the caudate and putamen, preferentially in the patch neurons; nevertheless, a low level of dynorphin mRNA is also present in neurons of the caudate matrix. Substance P mRNA is initially restricted to caudate neurons. At birth, both substance P and dynorphin mRNAs are expressed at high levels in the patches. These results demonstrate that each neuropeptide gene is expressed during human fetal life in neurons with a specific topology and pace of development in relation to caudate-putamen and patch-matrix differentiation. These results also contribute evidence that neurochemical evolution of the striatal neuronal populations is not complete at birth in humans.

Lhermitte-Duclos type cerebellum hamartoma and Cowden disease.

A Lhermitte-Duclos type cerebellum hamartoma is reported in a woman with a diffuse hamartomatous condition involving the breast, thyroid, colon, skin, and kidney. The family history demonstrated the autosomal dominant transmission of this hamartomatous syndrome, and indicated the diagnosis of Cowden disease. This observation supports the recent hypothesis of Lhermitte-Duclos disease associated with Cowden disease as being a single phakomatosis.

[Oncocytic carcinoma of the parotid gland]. / Carcinome oncocytaire de la glande parotide.

We report the case of an oncocytic carcinoma of the parotid gland affecting a sixty year old woman that was revealed by a right inferior facial paralysis. The histological features were observed in the parotid gland and in the right superior cervical nodes. The originality of this observation as compared to the other very rare cases of oncocytic carcinoma reported is the undoubtful malignant features present right away.

Leber's optic neuropathy associated with disseminated white matter disease: a case report and review.

Leber's hereditary optic neuropathy (LHON), a mitochondrial disease, is clinically characterized by a bilateral subacute loss of central vision consecutive to optic nerve involvement. In some cases of LHON, neurological features are reported including multiple sclerosis-like (MSL) phenotype. We report one additional male patient displaying LHON-MSL associated with the prevalent G11778A mutation and review the cases with expendable data published so far in the literature. We discuss the respective roles of inflammation and energetic metabolism dysregulation in the development of brain lesions. We propose to treat these patients early with both antioxidative and immunosuppressive drugs in order to avoid further handicap.

Primitive malignant fibrous histiocytoma of the neck with carotid occlusion and multiple cerebral ischemic lesions.

BACKGROUND: Emergence of a malignant tumor at the site of an operation is a rare event and most often arises in association with retained foreign material. CASE DESCRIPTION: We describe a patient who 1 year after a left carotid endarterectomy for typical atheromatous lesions presented with several transient ischemic attacks with stepwise worsening of the deficit and rapid death. A few weeks before, a tumor of the neck had appeared at the site of the previous endarterectomy. At postmortem examination, we found a malignant histiocytofibroma occluding the left carotid artery, with several recent ischemic foci in the corresponding cerebral hemisphere without metastasis or tumor emboli. CONCLUSIONS: This observation is unusual owing to the histological type of the neoplasm and to the circumstance of emergence of the neoplasm.

Peripheral neuropathy associated with mitochondrial disorders: 8 cases and review of the literature.

Forty-three cases of peripheral neuropathy (PN) have been reported in the literature with a proven mitochondria (mt) DNA mutation, and 21 had a peripheral nerve biopsy (PNB). We studied 8 patients, 1 of whom had severe sensory PN, 3 mild PN, and 4 subclinical PN. Nerve biopsy was performed in every case; all patients showed axonal degeneration and 4 showed features of primary myelin damage. In addition, there were 2 crystalline-like inclusions in the Schwann cell cytoplasm of a patient with MERRF, and 1 in a patient with multiple deletions on the mtDNA. There are 11 cases of PNB in the literature with axonal lesions, 5 with demyelination, and 4 with mixed lesions. One PNB was not modified. A few crystalline-like inclusions were seen in 1 case of MERRF. Such inclusions were first reported in the Schwann cell cytoplasm of unmyelinated fibers in a patient with Refsum disease and were considered to be modified mitochondria. However, their mitochondrial origin remains debatable.

Simultaneous development of two different B-cell lymphomas in a patient with acquired immune deficiency syndrome evidenced by molecular analysis.

We report a case of a man positive for the human immunodeficiency virus who rapidly died of lymphoma with cerebral, lung, and pericardic involvement. After autopsy, histopathological study of the different tumor sites showed the same morphological feature of immunoblastic lymphoma, with large areas of necrosis. In situ hybridization showed monotypic kappa light chain mRNA within lung lymphoma cells and monotypic lambda light chain mRNA within cerebral lymphoma cells. Polymerase chain reaction analysis showed two different immunoglobulin heavy chain gene rearrangements for lung and cerebral lymphoma. Here the simultaneous association of two malignant lymphomas derived from different B-cell clones indicates that molecular analysis of different tumor sites can distinguish between dissemination of the same lymphoma and simultaneous proliferation of different malignant B-cell clones.

Concurrent herpes simplex type 1 necrotizing encephalitis, cytomegalovirus ventriculoencephalitis and cerebral lymphoma in an AIDS patient.

Unlike cytomegalovirus (CMV) ventriculoencephalitis, herpes simplex virus type 1 necrotizing encephalitis has only rarely been observed in AIDS patients. A 40-year-old bisexual man was followed for an HIV1 infection from 1987 onwards. In June 1993 he was referred for sudden confusion, left hemiparesia and fever. The blood contained less than 10 CD4 lymphocytes/mm3. The patient remained comatose and febrile, and died 4 weeks later. In coronal sections of the brain there was necrosis of the internal parts of the left temporal lobe, necrosis of certain areas of the ventricular walls and a small tumor at the top of the right frontal lobe, which proved to be a polymorphic high-grade lymphoma. CMV ventriculoencephalitis lesions were prominent in the ventricular walls of the occipital lobes and there was a strong nuclear signal for CMV using in situ hybridization. Herpes simplex virus type 1 was shown in the nuclei and cytoplasm of certain neurons and astrocytes in the borders of the necrotized temporal lobe areas by immunohistochemistry, in situ hybridization and electron microscopy, whereas in situ hybridization and immunohistochemistry for CMV were negative in such areas. Necrotizing type 1 encephalitis must not be overlooked in immunodeficient patients.