Erin M. Simon

The CNS phenotype of X-linked Charcot-Marie-Tooth disease: more than a peripheral problem.

X-linked Charcot-Marie-Tooth disease (CMTX) is the second most common form of inherited demyelinating neuropathy, next to CMT type 1A, which is caused by duplication of the PMP22 gene.1 CMTX is caused by mutations in GJB1 , the gene encoding connexin32 (Cx32), which belongs to a highly conserved family of proteins that form gap junctions in vertebrates. Myelinating Schwann cells express Cx32, which likely forms gap junctions between the layers of the myelin sheath, thereby providing a shorter pathway for the diffusion of small molecules and ions directly across the myelin sheath.2 Oligodendrocytes also express Cx32, which participates in the gap junction coupling of oligodendrocytes and astrocytes.3 More than 240 different GJB1 mutations have been described (http://molgen-www.uia.ac.be/CMTMutations/DataSource/MutByGene.cfm). Most patients with CMTX, including those with a deletion of the GJB1 gene, have a similar degree of neuropathy, indicating that most mutations probably cause a loss of function.1 In agreement, many Cx32 mutants do not form functional gap junctions,4 often related to their aberrant trafficking to the cell membrane.5 In addition to their peripheral neuropathy, many patients have asymptomatic evidence of brain involvement, such as abnormal brainstem auditory evoked responses (BAER).6,7⇓ Patients have also been found to have abnormal brain MRI results in association with transient CNS symptoms.8-11⇓⇓⇓ Here, we report a patient who had two episodes resembling acute demyelinating encephalomyelitis (ADEM), the first episode preceding the diagnosis of CMTX. A 12-year-old boy presented in January 1999 with three consecutive episodes of transient neurologic dysfunction, over the course of 3 days, with complete recovery between each episode. Initially, he had numbness of the right face and arm, paresis of the right arm and face, and dysarthria, lasting 4 hours. The following day, he developed the same symptoms, and mild right leg …

Callosal agenesis with cyst A better understanding and new classification

Objective: To analyze imaging studies of 25 cases of agenesis of the corpus callosum with interhemispheric cyst to assess this malformation itself and associated anomalies. Methods: CT (6 patients) and MRI (19 patients) were retrospectively reviewed. The patients were categorized according to morphologic and clinical characteristics. Results: Based on morphology, the patients were separated into two major types, each with subtypes. Type 1 cysts appear to be an extension or diverticulation of the third or lateral ventricles, whereas Type 2 are loculated and do not communicate with the ventricular system. Type 1a were associated with presumed communicating hydrocephalus but no other cerebral malformations. Type 1b were associated with hydrocephalus secondary to diencephalic malformations prohibiting egress of CSF from the third ventricle into the aqueduct of Sylvius. Type 1c were associated with small head size and apparent cerebral hemispheric dysplasia or hypoplasia. Type 2a (multiloculated cysts) were associated with no abnormalities other than callosal agenesis/hypogenesis. Type 2b were associated with deficiencies of the falx cerebri, subependymal heterotopia, and polymicrogyria (and were almost all in patients diagnosed with Aicardi syndrome). Type 2c were associated with subcortical heterotopia. Type 2d consists of interhemispheric arachnoid cysts. Other than those with Type 2b cysts, gender predominance was overwhelmingly male. Conclusion: Agenesis of the corpus callosum with interhemispheric cyst appears to consist of a heterogeneous group of disorders that have in common callosal agenesis and extraparenchymal cysts, both of which are among the commonest CNS malformations. This article proposes a classification system, based primarily on morphology, by which this complex group of disorders might begin to be better understood.

Diffusion-weighted imaging in acute bacterial meningitis in infancy

Bacterial meningitis is frequently fatal or leads to severe neurological impairment. Complications such as vasculitis, resulting in infarcts, should be anticipated and dealt with promptly. Our aim was to demonstrate the complications of meningitis by diffusion weighted imaging (DWI) in patients who deteriorated despite therapy. We studied 13 infants between the ages of 1 day and 32 months who presented with symptoms ranging from fever and vomiting to seizures, encephalopathy and coma due to bacterial meningitis, performing MRI, including DWI, 2–5 days after presentation. Multiple infarcts were found on DWI in 12 of the 13, most commonly in the frontal lobes (in 10). Global involvement was seen in four children, three of whom died; the fourth had a very poor outcome. In one case abnormalities on DWI were due to subdural empyemas. We diagnosed vasculitis in three of five patients studied with MRA. We think DWI an important part of an MRI study in infants with meningitis. Small cortical or deep white-matter infarcts due to septic vasculitis can lead to tissue damage not easily recognized on routine imaging and DWI can be used to confirm that extra-axial collections represent empyemas.

Neuroanatomy of holoprosencephaly as predictor of function Beyond the face predicting the brain

BackgroundDespite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described. Objective To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function. Methods The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation. Results In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01). ConclusionsPatients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.

Middle interhemispheric variant of holoprosencephaly: A distinct cliniconeuroradiologic subtype

Background: The middle interhemispheric variant (MIH) is a subtype of holoprosencephaly (HPE) in which the posterior frontal and parietal areas lack midline separation, whereas more polar areas of the cerebrum are fully cleaved. While the neuroradiologic features of this subtype have been recently detailed, the clinical features are largely unknown. Objective: To present the clinical manifestations of MIH and to compare them with classic subtypes (alobar, semilobar, and lobar) of HPE. Methods: The authors evaluated 15 patients with MIH in a multicenter study. Neuroimaging and clinical data were collected and correlated. They compared the data with those of 68 patients who had classic HPE. Results: The frequency of endocrinopathy in MIH (0%) was lower compared with the classic subtypes (72%) (p < 0.0001). This correlated with the lack of hypothalamic abnormalities. The percentage of patients with seizures (40%) did not significantly differ from classic HPE. Spasticity was the most common motor abnormality, seen in 86% of MIH patients, similar to other subtypes. The frequency of choreoathetosis in MIH (0%) was lower than that for semilobar HPE (41%) (p < 0.0039). This correlated with the lack of caudate and lentiform nuclei abnormalities. Developmental functions, including mobility, upper-extremity function, and language, of the MIH group were similar to the least severe classic type, lobar HPE. Conclusion: MIH is a recognizable variant of HPE with differing clinical prognosis. Similar to the lobar subtype by functional measures, MIH differs from classic HPE by the absence of endocrine dysfunction and choreoathetosis.

The dorsal cyst in holoprosencephaly and the role of the thalamus in its formation

Abstract The dorsal cyst is poorly understood, although it is commonly encountered in holoprosencephaly. We endeavor to establish the role of diencephalic malformations in the formation of the dorsal cyst and speculate on the developmental factors responsible. We reviewed the imaging of 70 patients with holoprosencephaly (MRI of 50 and high-quality CT of 20). The presence or absence of a dorsal cyst, thalamic noncleavage and abnormal thalamic orientation were assessed for statistical association, using Fishers Exact Test and logistical regression. The presence of a dorsal cyst correlated strongly with the presence of noncleavage of the thalamus (P = 0.0007) and with its degree (P < 0.00005). There was a trend toward an association between abnormalities in the orientation of the thalamus and the dorsal cyst, but this was not statistically significant (P = 0.07). We speculate that the unseparated thalamus physically blocks egress of cerebrospinal fluid from the third ventricle, resulting in expansion of the posterodorsal portion of the ventricle to form the cyst.

MRI of the fetal spine

Magnetic resonance imaging of the fetal spine is a vital complement to fetal sonographic examination. Assessing the wide spectrum of spinal dysraphism, as well as spinal neoplasia, allows for more correct prenatal diagnoses, patient care planning, and patient counselling. Proper appraisal of the value of experimental procedures, such as fetal myelomeningocoele repair, requires a high level of diagnostic accuracy for the selection and follow-up of appropriate candidates.

Intramedullary cervical spine germinoma: case report.

OBJECTIVE AND IMPORTANCE:We report an extremely rare case of primary intramedullary germinoma in the cervical spinal cord arising in an 18-year-old man who had not undergone previous surgery or irradiation. CLINICAL PRESENTATION:The patient had a 2-month history of intermittent neck pain and a 4-week history of bilateral hand paresthesias and weakness. A magnetic resonance imaging scan demonstrated a heterogeneous cervical spine lesion with marked contrast enhancement extending from C3 to C6. INTERVENTION:The patient underwent a cervical laminotomy with tumor resection, and pathological examination revealed the tumor to be a germinoma. He recovered well from the surgery with minimal neurological deficits. A postoperative magnetic resonance imaging scan of the brain and spinal cord did not show any other tumors. In addition, imaging studies of the mediastinum, testes, and the rest of the body also did not demonstrate any other tumors. The patient received local radiation as well as three courses of chemotherapy. CONCLUSION:To our knowledge, this is the first report of an intramedullary cervical spine germinoma with confirmed tissue diagnosis. Although extremely uncommon, the possibility of germinoma should be included in the differential diagnosis for primary intramedullary spinal cord tumors.

Biotinidase deficiency: the importance of adequate follow-up for an inconclusive newborn screening result

Biotinidase deficiency is an inherited metabolic disorder characterized by inability to recycle protein-bound biotin. It usually presents with ataxia and seizures, though atypical presentations have also been described. We report a 15-month-old boy with profound biotinidase deficiency who presented with laryngeal stridor and subsequently developed severe ataxia and lactic acidosis. Subsequently, it was discovered that the patient’s newborn screening test for biotinidase activity had been inconclusive, but confirmatory testing had not been done. Brain magnetic resonance imaging showed multiple white matter non-enhancing T2 hyperintensities, which largely resolved following 6 months of biotin therapy; however, there was residual deafness and mental retardation. Conclusion:An argument is made for universal newborn screening in biotinidase deficiency and improved mechanisms for follow-up of positive screens, because delay in diagnosis results in irreversible morbidity, newborn screening is cost effective, and early therapy prevents the neurologic sequelae.

High-resolution 3D T2-weighted fast spin echo: new applications in the orbit

Recent developments have made available for ophthalmologic MR imaging a very high-resolution 3D fast spin echo T2 (3D FSE T2) sequence, which runs in a standard head coil. A modification of this technique, 3D FSEz T2, uses a zero-filled slice interpolation method during post-processing to further improve spatial resolution. We describe the technique and share our early clinical observations in patients with ocular masses. Briefly, the additional information from the 3D FSEz T2 resulted in a change in diagnosis from the conventional imaging series in 11 of (41%) 27 studies, usually through the identification of previously treated retinoblastoma lesions. The new sequence significantly increased diagnostic confidence in six (38%) of the remaining 16 cases, usually through better anatomical detail and lesion conspicuity, and did not change interpretation in 10 cases. Such an approach improves diagnostic confidence and may eliminate the need for a dedicated surface coil examination.