Diffuse Cerebral Atrophy Research Articles

Autopsy findings of a patient with acute encephalitis and refractory, repetitive partial seizures

Chikako Ogawa *, Jun Natsume , Hiroyuki Yamamoto , Naoko Ishihara , Atsushi Tashiro , Hiroyuki Kidokoro , Tamiko Negoro , Mari Yoshida , Kazuyoshi Watanabe a Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan Department of Pediatrics, Social Insurance Chukyo Hospital, Nagoya, Japan Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

An unusual cause for focal convulsions: Menkes kinky hair disease

A 6-month-old male infant was admitted to hospital with the history of repeated attacks of focal convulsions since 1 day prior to admission. He was also suffering from frequent attacks of cough and cold since 5 months of age, which was marked prior to admission. The infant had fair complexion, sparse fuzzy woolly hair with marked trunkal hypotonia. Serum copper and ceruloplasmin levels were low, magnetic resonance imaging showed diffuse cerebral atrophy with ill-defined areas of encephalomalacia. Microscopic examination of hair revealed pili torti. The patient was diagnosed as Menkes disease and treated symptomatically. For lack of facilities, we were not able to do magnetic resonance angiography and genetic study.

Pyridoxine-dependent seizures: an atypical case

Pyridoxine-dependent seizure (PDS) is a readily treatable cause of intractable seizures in childhood (1). Not more than 100 cases have been reported in the English language indexed journals. Delay in initiation of treatment could result in permanent mental handicap. It is generally recommended that a trial of pyridoxine should be given in all cases of intractable seizures below the age of 3 years (2). We report a case of 4-year-old boy with mental retardation and intractable seizures who, responded well to pyridoxine. This report emphasizes the importance of considering PDS in children with intractable seizures beyond 3 years. A 4-year-old boy was admitted to the pediatrics intensive care unit with status epilepticus. He was born to non-consanguineous parents with an Apgar score of 10 at 5 minutes. There was no family history of seizures or mental impairment. Child attained social smile at 4 months, turned over at 7 months, walked independently at 20 months, and started saying 2-3 words at 3 years. Generalized seizures (partial seizures with generalization and myoclonus) started at the age 2 years. Various antiepileptic drugs either as monotherapy or in combination resulted mild reduction in seizure frequency. At 4 years he could speak 3-4 words, could indicate toilet needs and walk with minimal difficulty. His vision and hearing were normal. Electroencephalogram (EEG) showed multifocal spike and wave discharges. MRI of brain showed mild diffuse cerebral atrophy with prominent ventricles. The following tests were normal or negative: hemogram, serum calcium and phosphorous, blood thyroid hormone profile, renal and liver function tests, serum ammonia, blood arterial pH, plasma organic acids, and urine homocysteine, reducing substances and organic acids. He was continued

Contactin-associated protein 2 (Caspr2) antibodies associated with refractory temporal seizures, rapid cognitive decline, and emotional lability

Background: Caspr2 is a transmembrane protein facilitating intercellular communication. It is found primarily in the central nervous system, specifically cerebellum and hippocampus. Anti-Caspr2 antibodies, more commonly seen in men (M/F: 4), also bind voltage-gated potassium channels. The antibodies are associated with limbic encephalitis, seizures, Morvan’s syndrome, peripheral nerve hyperexcitability, and cerebellar ataxia. Malignancy exists in 20% of cases. Methods: Case report and review of literature. Results: A 71-year-old man presented with subacute onset refractory seizures failing several anti-convulsants, emotional lability, and rapid decline in memory and executive function. EEG showed an electrographic seizure over the left hemisphere. MRI brain demonstrated mild diffuse cerebral atrophy, chronic ischemic changes, and mild diffusion restriction in the medial frontal lobes. Cerebrospinal fluid was normal. Serum Antithyroid peroxidase and antithyroglobulin antibodies were negative. TSH was slightly elevated and eltroxin didn’t help. Anti-Caspr2 antibodies were highly positive. EMG ruled out neuromyotonia. Body CT and PET scans indicated no malignancy. Treatment with IVIG stopped the seizures and cognition dramatically improved. Conclusions: Recognizing anti-Caspr2 antibody-associated encephalitis in elderly males with new onset refractory epilepsy and rapid cognitive decline is important for timely initiation of immunomodulation to avoid permanent deficits. Rapid executive dysfunction was unique in this case.

Clinical and imaging characteristics of 16 patients with autoimmune neuronal synaptic encephalitis.

Autoimmune neuronal synaptic encephalitis (AIE) encompasses a heterogeneous group of disorders characterized by immune-mediated neuronal cell destruction. In this study, we aim to study the clinical features, imaging profile and treatment outcome of patients with AIE. This is a chart review of 16 (M: F-3:13) patients with AIE from 2011 to 2015. Among the patients, 10 had anti-NMDA, 4 had anti-TPO, and 2 had anti-VGKC antibody positivity. Cognitive impairment and seizures were the predominant symptoms present in nearly all patients, followed by psychiatric disturbances (87.5%), mutism (62.5%), movement disorders (62.5%), myoclonic jerks (37.5%) and visual hallucinations (18.75%). Magnetic resonance imaging (MRI) of the brain was available in 15 patients; it was abnormal in 53.3% patients. Abnormalities were seen in all patients with anti-VGKC positivity; and, 60% of patients with anti-NMDA positivity. Imaging was normal in 26.7% of the patients (3: anti-NMDA; and, 1: anti-TPO positivity); and, diffuse cerebral atrophy was noted in rest of the 20% (3: anti-TPO positivity) patients. All patients improved gradually with immunomodulation. All patients with anti-VGKC, anti-NMDA and anti-TPO antibody positivity presented with a triad of behavioral changes, impaired cognition and seizures. Mutism was a predominant symptom in patients with an anti-NMDA antibody positivity, which may help in the early identification of this disorder. MRI brain showed changes restricted to limbic structures in anti-NMDA and anti-VGKC antibody positivity. An early diagnosis and treatment of autoimmune encephalitis is essential for a better outcome and for prevention of long-term sequel.

Rasmussen′s encephalitis: A rare case report

Rasmussen's encephalitis (RE) is a chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex leading to progressive neurological and cognitive deterioration. Advances in neuroimaging suggest that progression of the inflammatory process seen with magnetic resonance imaging (MRI) might be a good biomarker in RE. We present here a case of 8-year-old male child presented with repeated episodes of drug resistant seizures leading to intellectual impairment and cognitive deterioration. Further MRI was done which shows diffuse left cerebral atrophy.

Dacrystic Seizures and Psychogenic Non-Epileptic Seizures: A Case Report

Dacrystic seizures are rare clinical occurrences characterized by paroxysmal stereotyped crying with a special challenging differential diagnosis with psychogenic non-epileptic seizures (PNES). We present a report of a male 21-yearold patient with history of schizophrenia, agitation crises and apparent seizures comprising a myriad of consciousness, motor, visual and autonomic manifestations. The patient began to smoke cannabis at age 15 and at age 18 smoked crack for 6 months. The seizures began at approximately this time and were incapacitating. In intercritical periods, he was friendly, communicative and displayed hysterical personality traits, but examination indicated no negative or positive symptoms when abstinent. Cognitive assessments revealed presence of intellectual deficiency (current QI=75). During hospitalization, the patient was extensively examined, and the diagnosis of schizophrenia was ruled out. All antipsychotic drugs were gradually tapered off. Video- EEG monitoring captured a prolonged seizure compatible with a dacrystic seizure. A cranial MRI scan revealed discrete diffuse cerebral atrophy. Carbamazepine was introduced and titrated until 1,600 mg/day and patient has been seizure-free for about 12 months. This case illustrates the importance of differential diagnosis of putative psychogenic seizures. This is the first report of dacrystic epileptic seizures associated with PNES and comorbid abuse of crack.

Cognitive Impairment and Brain Imaging Characteristics of Patients with Congenital Cataracts, Facial Dysmorphism, Neuropathy Syndrome.

Congenital cataracts, facial dysmorphism, neuropathy (CCFDN) syndrome is a complex autosomal recessive multisystem disorder. The aim of the current study is to evaluate the degree of cognitive impairment in a cohort of 22 CCFDN patients and its correlation with patients' age, motor disability, ataxia, and neuroimaging changes. Twenty-two patients with genetically confirmed diagnosis of CCFDN underwent a detailed neurological examination. Verbal and nonverbal intelligence, memory, executive functions, and verbal fluency wеre assessed in all the patients aged 4 to 47 years. Brain magnetic resonance imaging was performed in 20 affected patients. Eighteen affected were classified as having mild intellectual deficit, whereas 4 had borderline intelligence. In all psychometric tests, evaluating different cognitive domains, CCFDN patients had statistically significant lower scores when compared to the healthy control group. All cognitive domains seemed equally affected. The main abnormalities on brain MRI found in 19/20 patients included diffuse cerebral atrophy, enlargement of the lateral ventricles, and focal lesions in the subcortical white matter, different in number and size, consistent with demyelination more pronounced in the older CCFDN patients. The correlation analysis of the structural brain changes and the cognitive impairment found a statistically significant correlation only between the impairment of short-term verbal memory and the MRI changes.

Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.

We describe a family with QARS deficiency due to compound heterozygous QARS mutations, including c.1387G > A (p.R463*) in the catalytic core domain and c.2226C > G (p.Q742H) in the anticodon domain, both previously unreported and predicted damaging. The phenotype of the male index further confirms this specific aminoacyl-transfer RNA (tRNA) synthetase disorder as a novel genetic cause of progressive microcephaly with diffuse cerebral atrophy, severely deficient myelination, intractable seizures, and developmental arrest. However, in contrast to the two hitherto published families, the cerebellum and its myelination are not affected. An awareness that QARS mutations may cause isolated supratentorial changes is crucial for properly directing genetic analysis.

Subdural Hemorrhage and Antithrombotic Therapy

Investigators at the Mott Children’s Hospital, Ann Arbor, MI, report 4 infants with diffuse brain injury and cerebral atrophy who developed cerebral venous sinus thrombosis and were treated with the low-molecular-weight heparin, enoxaparin.

English

INTRODUCTION: A 58 years old man with a no history of hearing loss was admitted with comminuted fracture tibia and fibula (right), sustained in a road traffic accident [Fig. 1]. He had no known comorbidity. The pre-operative history and physical examination, blood test investigations, chest radiograph [Fig. 2] and ECG were unremarkable. He was taken up for open reduction and pinning of fractured segments [Fig. 3]. The orthopedic surgery itself was uneventful with the patient being under general anesthesia for a total of one hour. Induction of anesthesia was uncomplicated, and blood loss was minimal. The blood pressure and pulse remained stable, with minimum diastolic and systolic pressure during surgery being 70 mmHg and 130 mmHg respectively. Oxygen saturation remained over 95 percent. In the post-operative ward, he received parenteral antibiotic cover with Inj Augmentin. Additionally he was given Inj Diclofenac for analgesia and Inj Ondensatron for nausea. Shortly after transfer to the ward, he complained of tinnitus and being unable to hear in either ear. There was no nausea, vomiting, or vertigo. An otolaryngology consultation at this time showed normal cranial nerve, cerebellar, oculomotor and fundoscopic exams. Audiometry showed bilateral profound 100 dB and 105 dB sensorineural hearing loss in the right and left ears respectively [Fig. 4]. Blood tests including sedimentation rate, coagulation profile, blood count, smear examination, lipid profile, serum thyroid hormone levels, renal and liver function tests were all normal. CT scan of skull was normal except for mild diffuse cerebral atrophy [Fig. 5, 6, 7]. He was placed on conservative management with oral steroids (50 mg/day) for 10 days. Serial audiograms of the patient thereafter showed mild improvement, with residual hearing loss in both ears of 80dB. After four weeks, there continues to be hearing loss in both ears [Fig. 8]. Speech comprehension continues to be difficult for the patient, with speech discrimination scores being less than 50 percent in both ears.

Pyramidal neurons of the prefrontal cortex in post-stroke, vascular and other ageing-related dementias.

Dementia associated with cerebrovascular disease is common. It has been reported that ∼30% of elderly patients who survive stroke develop delayed dementia (post-stroke dementia), with most cases being diagnosed as vascular dementia. The pathological substrates associated with post-stroke or vascular dementia are poorly understood, particularly those associated with executive dysfunction. Three separate yet interconnecting circuits control executive function within the frontal lobe involving the dorsolateral prefrontal cortex, anterior cingulate cortex and the orbitofrontal cortex. We used stereological methods, along with immunohistological and related cell morphometric analysis, to examine densities and volumes of pyramidal neurons of the dorsolateral prefrontal cortex, anterior cingulate cortex and orbitofrontal cortex in the frontal lobe from a total of 90 elderly subjects (age range 71-98 years). Post-mortem brain tissues from post-stroke dementia and post-stroke patients with no dementia were derived from our prospective Cognitive Function After Stroke study. We also examined, in parallel, samples from ageing controls and similar age subjects pathologically diagnosed with Alzheimer's disease, mixed Alzheimer's disease and vascular dementia, and vascular dementia. We found pyramidal cell volumes in layers III and V in the dorsolateral prefrontal cortex of post-stroke and vascular dementia and, of mixed and Alzheimer's disease subjects to be reduced by 30-40% compared to post-stroke patients with no dementia and controls. There were no significant changes in neuronal volumes in either the anterior cingulate or orbitofrontal cortices. Remarkably, pyramidal neurons within the orbitofrontal cortex were also found to be smaller in size when compared to those in the other two neocortical regions. To relate the cell changes to cognitive function, we noted significant correlations between neuronal volumes and total CAMCOG, orientation and memory scores and clinical dementia ratings. Total estimated neuronal densities were not significantly changed between patients with post-stroke dementia and post-stroke patients with no dementia groups or ageing controls in any of the three frontal regions. In further morphometric analysis of the dorsolateral prefrontal cortex, we showed that neither diffuse cerebral atrophy nor neocortical thickness explained the selective neuronal volume effects. We also noted that neurofilament protein SMI31 immunoreactivity was increased in post-stroke and vascular dementia compared with post-stroke patients with no dementia and correlated with decreased neuronal volumes in subjects with post-stroke dementia and vascular dementia. Our findings suggest selective regional pyramidal cell atrophy in the dorsolateral prefrontal cortex-rather than neuronal density changes per se-are associated with dementia and executive dysfunction in post-stroke dementia and vascular dementia. The changes in dorsolateral prefrontal cortex pyramidal cells were not associated with neurofibrillary pathology suggesting there is a vascular basis for the observed highly selective neuronal atrophy.

Successful Treatment of Catatonia in a Young Man With Schizophrenia and Progressive Diffuse Cerebral Atrophy

Successful Treatment of Catatonia in a Young Man With Schizophrenia and Progressive Diffuse Cerebral Atrophy

Lingual myoclonus and neuropsychiatric lupus: a new association?

Lingual myoclonus and neuropsychiatric lupus: a new association?

Panencephalopathic Creutzfeldt‐Jakob Disease with Distinct Pattern of Prion Protein Deposition in a Patient with D178N Mutation and Homozygosity for Valine at Codon 129 of the Prion Protein Gene

Prion diseases include sporadic, acquired and genetic forms linked to mutations of the prion protein (PrP) gene (PRNP). In subjects carrying the D178N PRNP mutation, distinct phenotypes can be observed, depending on the methionine/valine codon 129 polymorphism. We present here a 53-year-old woman with D178N mutation in the PRNP gene and homozygosity for valine at codon 129. The disease started at age 47 with memory deficits, progressive cognitive impairment and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years and the disease course was 6 years. The neuropathologic examination demonstrated severe diffuse cerebral atrophy with neuronal loss, spongiosis and marked myelin loss and tissue rarefaction in the hemispheric white matter, configuring panencephalopathic Creutzfeldt-Jakob disease. PrP deposition was present in the cerebral cortex, basal ganglia and cerebellum with diffuse synaptic-type pattern of immunoreactivity and clusters of countless, small PrP deposits, particularly evident in the lower cortical layers, in the striatum and in the molecular layer of the cerebellum. Western blot analysis showed the presence of type 1 PrP(Sc) (Parchi classification). These findings underline the clear-cut distinction between the neuropathological features of Creutzfeldt-Jakob disease associated with D178N PRNP mutation and those of fatal familial insomnia.

Clinical, Electrophysiological, Imaging, and Ultrastructural Description in 68 Patients With Neuronal Ceroid Lipofuscinoses and Its Subtypes

PurposeWe evaluated the clinical, electrophysiological, imaging, and ultrastructural features of neuronal ceroid lipofuscinoses and its subtypes. MethodsThe clinical, electrophysiological, imaging, histopathological, and ultrastructural features of 68 (age at onset: 4.3 ± 5.4 years) neuronal ceroid lipofuscinoses and its subtypes (infantile neuronal ceroid lipofuscinoses [9], late infantile neuronal ceroid lipofuscinoses [34], juvenile neuronal ceroid lipofuscinoses [23], and adult neuronal ceroid lipofuscinoses [2] were evaluated. Skin (n = 56), brain (n = 12), muscle (n = 4) and nerve (n = 1) biopsies confirmed the diagnosis. ResultsClinical manifestations were milestone regression (93%), involuntary movements (92%), seizures (89%), myoclonus (79%), and visual impairment (68%). Response to anticonvulsants was unsatisfactory. Electroencephalography (n = 59) was abnormal in 90%: background slowing (90%); epileptiform discharges (71%), and photoparoxysmal response (4/21). Visual-evoked (n = 33) and somatosensory evoked (n = 40) potentials were abnormal in 62% and 63% of patients. Cranial computed tomography (n = 33) showed diffuse cerebral (61%) and cerebellar (27%) atrophy. Magnetic resonance imaging was abnormal in all 43 patients who were scanned: diffuse atrophy (100%), cerebellar atrophy (40%), leukoencephalopathy (65%), and thalamic T2 W hypointensity (33%). Dermal inclusions such as curvilinear inclusions were the most common abnormality: late infantile neuronal ceroid lipofuscinoses (97%), juvenile neuronal ceroid lipofuscinoses (100%), and infantile neuronal ceroid lipofuscinoses (88%). Additional fingerprint inclusions were noted: juvenile neuronal ceroid lipofuscinoses (43%), late infantile neuronal ceroid lipofuscinoses (15%), and infantile neuronal ceroid lipofuscinoses (13%). Granular osmiophilic deposits were noted in 50% of infantile neuronal ceroid lipofuscinoses. In 75% of patients, there was good correlation between the clinical subtype and ultrastructural inclusion pattern. In 27% of neuronal ceroid lipofuscinoses, multiple inclusions were noted. ConclusionsThe diagnosis of neuronal ceroid lipofuscinoses should be considered in individuals with characteristic clinical presentations and characteristic ultrastructural dermal inclusions. Three fourths showed morphological correlation of the inclusions with neuronal ceroid lipofuscinoses subtype.

Seeing More Clearly Through the Fog of Encephalopathy

Patients with acute confusional states (often referred to as encephalopathy or delirium) pose diagnostic and management challenges for treating physicians. Encephalopathy is associated with a high morbidity and mortality rate, and the diagnosis rests on clinical grounds but may also be supported by the finding of electroencephalographic (EEG) evidence for diffuse cerebral dysfunction. The myriad cerebral transmitter and metabolic disruptions are generated by systemic organ system failures, principal among which are those of the liver, kidneys, lungs, heart, and endocrine system, along with the effects of exogenous toxins and medications. In most cases, several of these organ failures together contribute to the confusional state, frequently in the context of a diffuse cerebral atrophy that affects the aging brain. This special issue of the Journal of Clinical Neurophysiology is dedicated to exploring the electrophysiology of these conditions. It reviews the pathophysiology, psychiatric manifestations, clinical and imaging correlations of the many causes and types of encephalopathy. A literature review of the EEG abnormalities in the various types of encephalopathy provides an overview that ranges from paraneoplastic causes, through organ system failures, postcardiorespiratory arrest, to postoperative delirium. The issue is supplemented by tables of relevant clinical correlations, graphs, Venn diagrams, and the use of mathematical modeling used to explain how defects in the neuronal interplay might generate the EEG patterns seen in encephalopathy. We hope that this assembly will act as a springboard for further discussion and investigation into the EEG underpinnings, clinical correlations, diagnosis. and prognostication of these common and morbid disturbances of brain function.

Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE

DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next-generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot.

Memantine‐associated renal impairment in a patient with Alzheimer's disease

MEMANTINE, AN N-methyl-d-aspartate glutamate receptor antagonist, is used in many countries mainly for the treatment of Alzheimer's disease (AD).1 Because it is predominantly excreted unchanged via the kidneys, patients with decreased creatinine clearance (CCr) must be treated at lower dose of memantine. It is unclear, however, whether memantine itself causes renal dysfunction. We report herein a patient with AD and impaired renal function associated with memantine. The patient, a 68-year-old man, was admitted for dyspnea and edematous legs and we were consulted for his cognitive impairment and behavioral problems, such as excitement. His friend reported that he had had memory impairment and anomia starting a few years earlier, followed by difficulty in conceptual thinking, driving and shopping. Mini-Mental State Exam score was 13 and functional assessment staging was 6d (severe cognitive decline). Computed tomography showed diffuse and moderate cerebral atrophy. He was diagnosed with AD and prescribed memantine (5 mg/day initial dosage, 10 mg/day 7 days later). According to laboratory examinations at the beginning of memantine use, serum creatinine (Cr) and blood urea nitrogen (BUN) levels were in the normal range (1.1 mg/dL and 21.8 mg/dL, respectively), then increased gradually up to 1.5 mg/dL and 35.9 mg/dL, respectively, 14 days after induction of treatment. The patient had been diagnosed with diabetes mellitus at the age of 35, although serum fasting blood sugar and glycohemoglobin were in the normal range. Due to all these findings, we concluded that memantine treatment had worsened his renal function and it was discontinued. After memantine cessation, his renal function returned to normal. The most striking finding in this patient was that memantine itself had the potential to worsen renal impairment. In general, the normal dose for daily treatment of this drug is 20 mg, and 10 mg is recommended in patients with severe renal impairment, although no dosage adjustments are needed for patients with mild or moderate renal impairment.2 It should be taken into account that the presents renal dysfunction may have been caused by other factors such as dehydration. In fact, the present patient's serum Cr and BUN were slightly elevated at the time of admission (1.2 mg/dL and 29.3 mg/dL, respectively) and then normalized after he was given i.v. fluids. Because we could not completely exclude the possibility of chronic renal impairment, we used the lower dose of memantine (10 mg/day maximum). Nevertheless, memory impairment and behavioral and psychological symptoms of dementia had partially improved at the time of discontinuation of memantine therapy, which suggests that the concentration of memantine was higher than expected due to decreased renal clearance. In conclusion, although memantine is one of the most potent therapeutic agents for patients with AD and its potential side-effect requires further deliberation, renal function should be carefully monitored, especially in patients with complications.