Rapid Neurological Deterioration Research Articles

Vanishing white matter: a leukodystrophy due to astrocytic dysfunction.

VWM is one of the most prevalent leukodystrophies with unique clinical, pathological and molecular features. It mostly affects children, but may develop at all ages, from birth to senescence. It is dominated by cerebellar ataxia and susceptible to stresses that act as factors provoking disease onset or episodes of rapid neurological deterioration possibly leading to death. VWM is caused by mutations in any of the genes encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B). Although eIF2B is ubiquitously expressed, VWM primarily manifests as a leukodystrophy with increasing white matter rarefaction and cystic degeneration, meager astrogliosis with no glial scarring and dysmorphic immature astrocytes and increased numbers of oligodendrocyte progenitor cells that are restrained from maturing into myelin-forming cells. Recent findings point to a central role for astrocytes in driving the brain pathology, with secondary effects on both oligodendroglia and axons. In this, VWM belongs to the growing group of astrocytopathies, in which loss of essential astrocytic functions and gain of detrimental functions drive degeneration of the white matter. Additional disease mechanisms include activation of the unfolded protein response with constitutive predisposition to cellular stress, failure of astrocyte-microglia crosstalk and possibly secondary effects on the oxidative phosphorylation. VWM involves a translation initiation factor. The group of leukodystrophies due to defects in mRNA translation is also growing, suggesting that this may be a common disease mechanism. The combination of all these features makes VWM an intriguing natural model to understand the biology and pathology of the white matter.

Early and late outcomes after cord blood transplantation for pediatric patients with inherited leukodystrophies

AbstractLeukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013. Factors associated with higher overall survival (OS) included presymptomatic status (77% vs 49%; P = .006), well-matched (≤1 HLA mismatch) CB units (71% vs 54%; P = .009), and performance status (PS) of >80 vs <60 or 60 to 80 (69% vs 32% and 55%, respectively; P = .003). For patients with PS≤60 (n = 20) or 60 to 80 (n = 24) pre-CBT, only 4 (9%) showed improvement. Of the survivors with PS >80 pre-CBT, 50% remained stable, 20% declined to 60 to 80, and 30% to <60. Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts. Early identification and fast referral to a specialized center may lead to earlier treatment and, subsequently, to improved outcomes.

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

BackgroundIn X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.MethodsWe enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2–3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.ResultsA total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.ConclusionsEarly results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102; ClinicalTrialsRegister.eu number, 2011-001953-10.)

P.045 Case of cavernous malformation hemorrhage immediately following normal brain imaging

Background: Spontaneous hemorrhage from angiographically occult vascular malformations is not a rare occurrence. We present a case of in-hospital cavernous malformation rupture after initial normal CT. Methods: A 55-year-old female presented with severe headache with onset during activity, and normal neurological examination. Rapid neurological deterioration occurred 60 minutes following the CT scan. The patient was intubated, and repeat CT scan showed significant parafalcine ICH and intrahemispheric SAH. ICU transfer and expectant management led to neurological recovery and discharge to rehabilitation. Results: The patient underwent angiography on initial admission which was negative. A delayed MRI showed the presence of a cavernous malformation. This was followed conservatively with repeat imaging. The malformation remained stable. Conclusions: Our unique case highlights the sudden onset of hemorrhage occurring almost immediately following normal brain imaging. A cavernous malformation was discovered to be the cause, and was observed.

Current Diagnosis and Management of Cervical Spondylotic Myelopathy.

Study Design:Review.Objectives:Cervical spondylotic myelopathy (CSM) is a major cause of disability, particular in elderly patients. Awareness and understanding of CSM is imperative to facilitate early diagnosis and management. This review article addresses CSM with regard to its epidemiology, anatomical considerations, pathophysiology, clinical manifestations, imaging characteristics, treatment approaches and outcomes, and the cost-effectiveness of surgical options.Methods:The authors performed an extensive review of the peer-reviewed literature addressing the aforementioned objectives.Results:The clinical presentation and natural history of CSM is variable, alternating between quiescent and insidious to stepwise decline or rapid neurological deterioration. For mild CSM, conservative options could be employed with careful observation. However, surgical intervention has shown to be superior for moderate to severe CSM. The success of operative or conservative management of CSM is multifactorial and high-quality studies are lacking. The optimal surgical approach is still under debate, and can vary depending on the number of levels involved, location of the pathology and baseline cervical sagittal alignment.Conclusions:Early recognition and treatment of CSM, before the onset of spinal cord damage, is essential for optimal outcomes. The goal of surgery is to decompress the cord with expansion of the spinal canal, while restoring cervical lordosis, and stabilizing when the risk of cervical kyphosis is high. Further high-quality randomized clinical studies with long-term follow up are still needed to further define the natural history and help predict the ideal surgical strategy.

Amyloid- and FDG-PET in sporadic Creutzfeldt-Jakob disease: Correlation with pathological prion protein in neuropathology

ABSTRACTIntroduction. The role of positron emission tomography (PET) in Creutzfeldt-Jakob disease is less defined than in other neurodegenerative diseases. We studied the correlation between the uptake of 18F-florbetaben and 18F-fluorodeoxyglucose with pathological prion protein deposition in histopathology in a case.Methods. A patient with 80 y old with a rapid neurological deterioration with a confirmed diagnosis of CJD was studied. PET and MRI studies were performed between 13–20 d before the death. A region of interest analysis was performed using Statistical Parametric Mapping.Results. MRI showed atrophy with no other alterations. FDG-PET showed extensive areas of hypometabolism including left frontoparietal lobes as well as bilateral thalamus. Correlation between uptake of 18F-florbetaben and pathological prion protein deposition was r = 0.786 (p < 0.05). Otherwise, correlation between uptake of 18F-FDG and pathological prion protein was r = 0.357 (p = 0.385). Immunohistochemistry with β-amyloid did not show amyloid deposition or neuritic plaques.Conclusions. Our study supports the use of FDG-PET in the assessment of CJD. FDG-PET may be especially useful in cases of suspected CJD and negative MRI. Furthermore, this case report provides more evidence about the behavioral of amyloid tracers, and the possibility of a low-affinity binding to other non-amyloid proteins, such as the pathological prion protein, is discussed.

Cervical Spondylodiscitis: Presentation, Timing, and Surgical Management in 59 Patients.

Cervical spondylodiscitis is thought to carry a significant risk for rapid neurologic deterioration with a poor response to nonsurgical management. A retrospective surgical case series of the acute surgical management of cervical spondylodiscitis isreviewed to characterize the neurologic presentation and postoperative neurologic course in a relatively uncommon disease. Fifty-nine patients were identified (mean age, 59 years [range, 18-83 years; SD ± 13.2 years]) from a single-institution neurosurgical database. The most common levels of radiographic cervical involvement were C4-C5, C5-C6, and C6-C7, in descending order. Overall, statistically significant clinical improvement was noted after surgery (P < 0.05). Spinal cord hyperintensity on T2-weighted magnetic resonance imaging was significantly associated with a worse preoperative neurologic grade (P= 0.036), but did not correlate with a relatively worse neurologic outcome by discharge. No significant difference was noted between potential preoperative predictors (organism cultured, presence of epidural abscess, tobacco use, early surgery within 24 hours of clinical presentation) and preoperative American Spinal Injury Association injury scale, with the exception of the duration between symptom onset and surgical intervention. Anegative correlation between increased preoperative duration of symptoms and magnitude in motor improvement was observed. Relative to anteroposterior decompression and fusion, anterior treatment alone demonstrated a relatively greater effect in neurologic improvement. Cervical spondylodiscitis is a rare disease that typically manifests with preoperative motor deficits. Surgery was associated with a significant improvement in motor score by hospital discharge. Significant predictors of neurologic improvement were not observed. Prolonged symptomatic duration was correlated with a significantly lower likelihood of motor score improvement.

Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients

BackgroundAlternating Hemiplegia of Childhood (AHC) is a severe disorder. Several drugs have been administered as prophylaxis for paroxysmal attacks, however, no therapy is completely effective. MethodsOur aim is to review the pharmacological data related to the prophylactic and acute treatment of a cohort of 30 patients (16M, 14F, age range 5–42years) and to correlate them with the clinical and genetic data collected through the Italian Biobank and Clinical Registry for AHC. ResultsFlunarizine was the most commonly used long-term treatment in the cohort; it reduced duration and frequency of attacks in 50% of patients and decreased intensity in 32.1%. In younger patients, flunarizine seemed significantly more effective in reducing intensity. We found no correlation between the effectiveness of flunarizine and genotype, or between developmental outcome and duration of treatment. In particular, 3 of our patients affected by E815K mutation presented rapid neurological deterioration despite ongoing treatment. Among the other administered prophylactic therapies, few proved to be effective (benzodiazepines, niaprazine, acetazolamide, melatonin, olanzapine, ketogenic diet). No clear rationale exists regarding their use, but these therapies may work by reducing the triggering factors. ConclusionsThe presented data are retrospective, but they are aimed at filling a gap given the rarity of the disease and the lack of randomized and controlled studies. Besides their usefulness in clarifying the pathophysiology of the disease, prospective studies involving larger cohorts of ATP1A3 mutated AHC patients are needed to provide a rationale for testing other molecules.

The First Reported Case of Second Impact Syndrome: A Reexamination of Dr Fekete's Case Report from 1968

Background In the December 28, 1968 edition of the Canadian Medical Association Journal, Dr John Fekete described a 16-year-old hockey player with fatal cerebral edema following a brain impact while actively symptomatic of a concussion incurred 4 days ago. This case has been described as a “possible” case of second impact syndrome, an entity that was named in 1984 and purportedly first described by Schneider in 1973. Method An audit of material in the public register of Dr Fekete's case was undertaken. Information sources included the newspaper report of the death, transcripts from a coroner's inquest held 12 days later, including the autopsy report, genealogical data available online, and available internet resources. Results There was clear documentation of concussive symptomatology following an initial head injury and evidence of a medical assessment, thus fulfilling the “definite” clinical criteria for second impact syndrome as proposed. After 4 days of ongoing concussive symptomatology, a dramatic, rapid neurological deterioration took place following an apparently unremarkable body contact and fall on the ice while playing hockey. His primary brain pathology included cerebral edema. Conclusion Cerebral edema may follow primary or secondary head injury, the latter comprising second impact syndrome. Dr Fekete's case, as described in the December 28, 1968 edition of the Canadian Medical Association Journal, should be recognized as the first description of this condition.

A Patient with Malignant Spinal Epidural Lymphoma with Initial Rapidly Aggravating Paraplegia

We report the case of a 51-year-old female with rapid neurological deterioration as an initial presentation of non-Hodgkin’s lymphoma. Paraplegia occurred suddenly after a 4-day history of weakness and numbness of the lower extremity. MRI revealed a dorsal epidural mass from T10 to T11 that compressed the spinal cord. There was neither bone destruction nor a paravertebral mass. Emergency decompressive laminectomy and tumor resection were performed. Histological analysis of the surgical specimen indicated diffuse large B cell lymphoma. The clinical stage was IV on CT and complete remission was achieved by subsequent chemotherapy. Spinal cord compression occurs in the course of non-Hodgkin’s lymphoma in 0.1% - 6.5% of cases, but this situation usually develops in the late phase with bone destruction and/or a paravertebral mass. Cord compression and especially the severe symptoms such as paraplegia are rare as the initial presentation of lymphoma.

Cerebral Fat Embolism in a Trauma Patient with Captured Imaging of Echogenic Emboli in the Inferior Vena Cava

The authors present a case of fat embolism syndrome after traumatic long-bone fracture in a patient with rapid neurologic deterioration and multiple cerebral embolic events. Diagnostic workup revealed the neuroradiologic findings classically described with cerebral fat emboli. The authors present hallmark ultrasound imaging of echogenic material actively traveling through the inferior vena cava.

Linfoma intravascular de células B grandes como causa inusual de ictus isquémico

Intravascular lymphoma is a type of extranodal lymphoma, usually composed of B-cells, resulting from a proliferation of atypical lymphocytes within the lumina of small to medium sized vessels. Since its initial description in 1959, it has had many names but currently the World Health Organization refers to this entity as intravascular large B-cell lymphoma. We present a case which presented with rapid progressive neurological deterioration and consecutive progressive multifocal and recurrent ischemic events of unknown origin. The postmortem study of the cranial cavity revealed atypical cell proliferation within the lumina of small to medium sized vessels. The lymphoid origin of intravascular tumor cells was confirmed by immunohistochemistry, establishing a diagnosis of intravascular large B-cell lymphoma.

Unusual case of cerebral venous thrombosis

Cerebral venous thrombosis (CVT) represents less than 5% of all strokes. Isolated cerebral deep venous thrombosis is very rare. Most patients present with rapid neurological deterioration. Early diagnosis and treatment may avoid potentially devastating consequences. Thrombosis of the cerebral deep venous system presenting with bilateral thalamic and basal ganglia infarction or oedema is not uncommon. We present a case of CVT with extensive involvement of basal ganglia, thalami and corpus callosum.

Acute necrotizing encephalopathy of childhood

Acute necrotizing encephalopathy of childhood (ANEC) is a rare form of encephalopathy characterized by rapid neurological deterioration along with seizures, decreased level of consciousness and coma. We herein report ANEC in a 12- month-old Iranian girl following febrile respiratory illness. She presented with convulsions characterized by upward gaze, spastic posture and sucking movements followed by rapid deterioration of consciousness and hemodynamic instability due to involvement of brainstem. Although several cases have been reported from East Asian countries, it has been rarely reported from Middle East region. This is the third case being reported from Iran. The diagnosis of ANEC should be kept in mind in all children with progressive neurological deterioration following a febrile convulsion. Although neuroradiological findings might be non-specific especially in early course of the disease, brain imaging should be performed when there is suspicion regarding the diagnosis.

Small vessel primary angiitis of the central nervous system: Rapidly progressing disease in a child

Primary angiitis of the central nervous system (CNS) is a recently described and rare disease in children. It is confined to the CNS and its etiology is unknown. A 10-year-old boy, previously healthy, presented with fever, headache and focal sei- zures, followed by left hemiparesis and central facial palsy. Brain magnetic resonance imaging (MRI) showed a large parie- tooccipital, cortical and subcortical lesion, hyperintense in T2-weighted/fluid attenuated inversion recovery imaging. Subse- quently, he presented a rapid neurological deterioration by weekly relapses, having several focal seizures, worsening of previous deficits and appearance of new ones on the right hemibody. He became aphasic and developed encephalopathy. Accordingly, MRI showed an extension of the previous lesion and appearance of new ones on the left hemisphere. He was initially treated with broad spectrum antibiotics and later immunoglobulin, methylprednisolone pulses and daily oral prednisolone, without sustained improvement. Etiologic investigations, including infectious or neurometabolic disease and systemic vasculitis were negative. Cerebral angiography was normal. A lesional biopsy confirmed a small vessel primary angiitis of the CNS. Seven wk after symptom onset, he was started on monthly cyclophosphamide (seven pulses) with prednisolone, achieving clinical stabilization. Mycophenolate mophetil was then substituted for cyclosphosphamide for 18 months. During a 2-year follow-up, no new clinical or imaging deterioration has been noted. Motor deficits have improved significantly but severe expression aphasia and cognitive deficit remains. He also developed refractory multifocal epilepsy. Small vessel primary angiitis of the CNS should be considered in a child with rapidly progressing acquired neurologic deterioration, multifocal inflammatory lesions on MRI and normal angiography. Prompt diagnosis and aggressive treatment is crucial for a favorable outcome.

Emergent Burr Hole Drainage of Traumatic Acute Subdural Hematoma with Drain Placement in Preexisting Coagulopathy Showing Rapid Neurological Deterioration: A Novel Technique

Emergent Burr Hole Drainage of Traumatic Acute Subdural Hematoma with Drain Placement in Preexisting Coagulopathy Showing Rapid Neurological Deterioration: A Novel Technique

Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype.

BackgroundTTC19 deficiency is a progressive neurodegenerative disease associated with isolated mitochondrial respiratory chain (MRC) complex III deficiency and loss-of-function mutations in the TT19 gene in the few patients reported so far.MethodsWe performed exome sequencing and selective mutational analysis of TTC19, respectively, in patients from three unrelated families presenting with initially unspecific clinical signs of muscular hypotonia and global developmental delay followed by regression, ataxia, loss of speech, and rapid neurological deterioration. One patient showed severe lactic acidosis at the neonatal age and during intercurrent illness.ResultsWe identified homozygous mutations in all three index cases, in two families novel missense mutations (c.544 T > C/p.Leu185Pro; c.917 T > C/p.Leu324Pro). The younger sister of the severely affected patient 3 showed only mild delay of motor skills and muscular hypotonia so far but is also homozygous for the same mutation. Notably, one patient revealed normal activities of MRC complex III in two independent muscle biopsies. Neuroimaging of the severely affected patients demonstrated lesions in putamen and caudate nuclei, cerebellar atrophy, and the unusual finding of hypertrophic olivary nuclei degeneration. Reviewing the literature revealed striking similarities regarding neuroimaging and clinical course in pediatric patients with TTC19 deficiency: patterns consistent with Leigh or Leigh-like syndrome were found in almost all, hypertrophic olivary nucleus degeneration in all patients reported so far. The clinical course in pediatric patients is characterized by an initially unspecific developmental delay, followed by regression, progressive signs and symptoms of cerebellar, basal ganglia and brainstem affection, especially loss of speech and ataxia. Subsequently, neurological deterioration leading to a vegetative state occurs.ConclusionsOur findings add to the phenotypic, genetic, and biochemical spectrum of TTC19 deficiency. However, TTC19 deficient patients do show characteristic clinical and neuroimaging features, which may facilitate diagnosis of this yet rare disorder. Normal MRC complex III activity does not exclude the diagnosis.

Experiences and conceptualisation of spinal intramedullary tuberculoma management.

ObjectiveSpinal intramedullary tuberculoma (SIMT) is rare, accounting for 2/100,000 cases of tuberculosis and only 0.2% of all cases of central nervous system(CNS) tuberculosis. We share our experiences of 11 cases of this entity for improving diagnosis and conceptualize the management of this rare disease.MethodsThe clinical profile, radiological data and management of 11 cases of SIMT which were managed either conservatively or by surgical intervention during last 27 years (1987-2014) were analysed.ResultsMale:female ratio was 1.75:1. Five cases had associated pulmonary Koch's. Most common site was thoracic cord. Two cases had concurrent multiple intracranial tuberculoma. Most common presentation was paraparesis. X-ray myelography was performed in two patients in the initial period of study suggesting intramedullary pathology. In the subsequent nine cases who had magnetic resonance imaging (MRI), seven showed typical "target sign" and conglomerate ring lesion. Out of 8 surgically managed patients, 6 cases improved rapidly and in 2 patients gradual improvement was seen in follow-up. Most common indication of surgical excision was rapid neurological deterioration followed by diagnosis in doubt. Histopathology confirmed tuberculous etiology of the intramedullary lesion in all. Clinical and radiological improvement was seen in all 3 conservatively managed patients in follow-up.ConclusionMRI findings of SIMT were specific and proven histologically correct. Surgical intervention may be indicated if there is no response to chemotherapy, the diagnosis is in doubt, or there is a rapid deterioration in neurological function because surgical outcome is good in these circumstances.

WITHDRAWN: Emergent burr-hole drainage of traumatic acute subdural haematoma with drain placement in pre-existing coagulopathy showing rapid neurological deterioration: A novel technique

“The Indian Journal of Neurotrauma is now published by Thieme Medical Publishers. Please contact Thieme publishers for further details.” The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy .

Penetrating shrapnel injuries of the posterior fossa.

Gunshot injuries of the posterior fossa are rare and may follow a fatal course. In posterior fossa gunshot injuries, cerebellar hematoma, contusion, obstruction of cerebrospinal fluid (CSF) circulation by the shrapnel, and intracranial hypertension caused by autoregulation loss lead to mortality in the early stage. In this study, four cases of patients who underwent surgical intervention after penetrating shrapnel injuries of the pure posterior fossa were evaluated. All of the patients were male; their mean age was 26.5 ± 5 years. The lowest and highest Glasgow Coma Scale scores were 4 and 12, respectively. Neural injury was detected by computed tomography performed after systemic and neurological examination following admission to the emergency service. The shrapnel was found in the cerebellar tissue in three cases and in the fourth ventricle in one case. Following preoperative procedures, surgery was performed with the patient in the prone position. Postoperative monitoring revealed no CSF fistula, meningitis, or hydrocephalus. None of the patients required revision surgery. There were no postoperative mortalities. Due to the small volume of the posterior fossa, acute pathologies may lead to rapid neurological deterioration and death. Early surgical intervention and close postoperative follow-up after penetrating shrapnel injuries of the posterior fossa play a significant role in reducing mortality and morbidity.