A case of disseminated microscopic demyelination with multifocal dystrophic calcification.

We present a 47-year-old woman with a 10-year disease course consisting of episodic confusion, aphasia, psychosis, depression, migrainous headaches and seizures. There was mild elevation of protein levels in the cerebrospinal fluid, progressive cerebral atrophy, and numerous small T1 hypointensities appearing as central "holes" in the corpus callosum on magnetic resonance imaging. She eventually expired due to status epilepticus and subsequent significant respiratory complications. In the central nervous system, there was generalized brain atrophy, and patchy labeling of blood vessels by antibodies to complement component 4d (C4d) and membrane attack complex. Innumerable small patches with loss of cell bodies (neurons and glial cells in gray matter and glial cells in white matter) and demyelination were scattered throughout the brain and spinal cord. There was no cavitation and the passing axons were mostly preserved. Large solid calcified foci were present predominantly in the pons along with disseminated focal calcification involving neuron cell bodies, neurites, and capillaries. Patchy labeling of glial cells and linear structures suggestive of myelin sheaths with C4d antibodies was observed while immunostains for SV40, tau, ß-amyloid, alpha synuclein, p62, and trans-activation response DNA-binding protein 43 kDa were negative. Whole-exome sequencing did not reveal any clinically significant variants. Although the radiological findings are suggestive of Susac's syndrome (a rare condition characterized by encephalopathy, hearing loss, and branch retinal artery occlusion), in the absence of audiovisual manifestations, a definitive diagnosis cannot be rendered and therefore, this case may be representing a new entity. Further reports of similar cases are needed for clarification.

Case report: Neuronal intranuclear inclusion disease initially mimicking reversible cerebral vasoconstriction syndrome: serial neuroimaging findings during an 11-year follow-up.

Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder known for its diverse clinical manifestations. Although episodic neurogenic events can be associated with NIID, no reported cases have demonstrated concurrent clinical features or MRI findings resembling reversible cerebral vasoconstriction syndrome (RCVS). Here, we present the inaugural case of an adult-onset NIID patient who initially displayed symptoms reminiscent of RCVS. The 59-year-old male patient's initial presentation included a thunderclap headache, right visual field deficit, and confusion. Although his brain MRI appeared normal, MR angiography unveiled left posterior cerebral artery occlusion, subsequently followed by recanalization, culminating in an RCVS diagnosis. Over an 11-year period, the patient encountered 10 additional episodes, each escalating in duration and intensity, accompanied by seizures. Simultaneously, cognitive impairment progressed. Genetic testing for NIID revealed an abnormal expansion of GGC repeats in NOTCH2NLC, with a count of 115 (normal range, <60), and this patient was diagnosed with NIID. Our report highlights that NIID can clinically and radiologically mimic RCVS. Therefore, in the differential diagnosis of RCVS, particularly in cases with atypical features or recurrent episodes, consideration of NIID is warranted. Additionally, the longitudinal neuroimaging findings provided the course of NIID over an 11-year follow-up period.

Episodic Neurological Dysfunction in X-Linked Charcot-Marie-Tooth Disease: Expansion of the Phenotypic and Genetic Spectrum.

BACKGROUND AND PURPOSE: X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1. METHODS: Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. RESULTS: We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2-45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. CONCLUSIONS: These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

Systematic review of CMTX1 patients with episodic neurological dysfunction.

OBJECTIVE: X-linked Charcot-Marie-Tooth type 1 (CMTX1) is an inherited peripheral neuropathy caused by mutations in the gap junction beta 1 (GJB1) gene, which encodes the connexin32 protein. A small number of patients with GJB1 mutations present with episodic neurological dysfunction and reversible white matter lesions, which has not been adequately reported. Here, we aim to enable clinicians to further understand this particular situation through systematically reviewing all published relevant cases. METHODS: We conducted a comprehensive search of the PubMed electronic database for medical literature relevant to CMTX1 patients with episodic neurological dysfunction and then fully analyzed the general information, clinical manifestations, and characteristics of magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and nerve conduction study (NCS). RESULTS: We identified 47 cases of CMTX1 associated with episodic central nervous system (CNS) dysfunction from 38 publications. CMTX1 patients experienced episodic CNS deficits at a young age, ranging from infancy to 26 years, and 45 (95.7%) of them were male. The CNS symptoms manifested as facial, lingual, or limb weakness in 44 (93.6%), dysarthria or dysphagia in 39 (83.0%), facial or limb numbness in 15 (31.9%), and ataxia in 10 (21.3%) patients. The duration of episodic symptoms ranged from 3 minutes to 6 months. Thirty (63.8%) CMTX1 cases have reported obvious predisposing factors, among which the most common factors were infection or fever (27.7%), travel to high altitude (12.8%), and intensive exercise (8.5%). As for brain MRI, most abnormal signals were found in bilateral deep white matter (88.9%) and corpus callosum (80.0%). In addition, most of the NCS results were abnormal, including prolonged latency, reduced amplitude, and slowed conduction velocity. The motor nerve conduction velocity (MNCV) of median nerve was the most detectable and valuable, ranging from 25 to 45 m/s. INTERPRETATION: We have reported the most comprehensive summary of the demographic and clinical profile from 47 CMTX1 patients with episodic CNS deficits and provided new insight into the phenotype spectrum of CMTX1. We hope that our study can help clinicians make early diagnosis and implement the best prevention and treatment strategies for CMTX1 patients with episodic CNS deficits.