Manuel Delgado-Alvarado

Progressive multifocal leukoencephalopathy and idiopathic CD4 lymphocytopenia

Idiopathic CD4 lymphocytopenia (ICL) is a syndrome described in patients with low counts of CD4 cells and no other causes for immunosuppression. A few cases of progressive multifocal leukoencephalopathy (PML) have been described in association with this entity. There is no effective treatment for any of them, and the clinical course and outcome are unpredictable. We report on a case of ICL with PML and review the literature, trying to identify the clinical features and the prognosis clues associated to these entities together. A 72-year-old man presented with acute onset gait instability that progressed to a severe cerebellar syndrome with cognitive decline. A cranial MRI showed findings consistent with PML, this diagnosis being confirmed by CSF analyses. Absolute number of CD4+ was 242 cells/μL. An extensive work-up including HIV tests was negative. Ten cases of PML and ICL have previously been reported. Factors contributing to the different outcomes are unknown. Although an effective treatment does not exist for PML, it has been recently demonstrated in vitro that several 5HT2A-receptor antagonists block the JC virus infection. Our patient greatly improved and remains stable 34 months after onset; we describe the potential role of mirtazapine in the treatment of PML.

Biomarkers for dementia and mild cognitive impairment in Parkinson's disease.

Cognitive decline is one of the most frequent and disabling nonmotor features of Parkinsons disease. Around 30% of patients with Parkinsons disease experience mild cognitive impairment, a well‐established risk factor for the development of dementia. However, mild cognitive impairment in patients with Parkinsons disease is a heterogeneous entity that involves different types and extents of cognitive deficits. Because it is not currently known which type of mild cognitive impairment confers a higher risk of progression to dementia, it would be useful to define biomarkers that could identify these patients to better study disease progression and possible interventions. In this sense, the identification among patients with Parkinsons disease and mild cognitive impairment of biomarkers associated with dementia would allow the early detection of this process. This review summarizes studies from the past 25 years that have assessed the potential biomarkers of dementia and mild cognitive impairment in Parkinsons disease patients. Despite the potential importance, no biomarker has as yet been validated. However, features such as low levels of epidermal and insulin‐like growth factors or uric acid in plasma/serum and of Aß in CSF, reduction of cerebral cholinergic innervation and metabolism measured by PET mainly in posterior areas, and hippocampal atrophy in MRI might be indicative of distinct deficits with a distinct risk of dementia in subgroups of patients. Longitudinal studies combining the existing techniques and new approaches are needed to identify patients at higher risk of dementia.

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches.

Dopaminergic treatment in Parkinsons disease (PD) reduces the severity of motor symptoms of the disease. However, its chronic use is associated with disabling motor and behavioral side effects, among which levodopa-induced dyskinesias (LID) and impulse control disorders (ICD) are the most common. The underlying mechanisms and pathological substrate of these dopaminergic complications are not fully understood. Recently, the refinement of imaging techniques and the study of the genetics and molecular bases of LID and ICD indicate that, although different, they could share some features. In addition, animal models of parkinsonism with LID have provided important knowledge about mechanisms underlying such complications. In contrast, animal models of parkinsonism and abnormal impulsivity, although useful regarding some aspects of human ICD, do not fully resemble the clinical phenotype of ICD in patients with PD, and until now have provided limited information. Studies on animal models of addiction could complement the previous models and provide some insights into the background of these behavioral complications given that ICD are regarded as behavioral addictions. Here we review the most relevant advances in relation to imaging, genetics, biochemistry and pharmacological interventions to treat LID and ICD in patients with PD and in animal models with a view to better understand the overlapping and unique maladaptations to dopaminergic therapy that are associated with LID and ICD.

Parkinsonism, cognitive deficit and behavioural disturbance caused by a novel mutation in the polymerase gamma gene

Polymerase γ (POLG) is the enzyme responsible for the replication and maintenance of mitochondrial DNA (mtDNA). Mutations in the POLG1 gene can lead to mitochondrial dysfunction, producing a wide range of neurological and non-neurological phenotypes. Neurological manifestations include ataxia, muscular weakness, epilepsy, progressive external ophthalmoplegia (PEO), ptosis, neuropathy, psychiatric disorders and, more rarely, parkinsonism. We present the case of an 80-year old female patient with a history of PEO, ptosis, childish behaviour, obsessive disorder, cognitive decline, and parkinsonism. A comprehensive study showed striatal dopamine deficiency on DaT Scan and ragged red fibres as evidenced by Gomori staining in a biopsy of the biceps brachii. Multiple deletions of mtDNA were detected, and sequencing of the POLG1 gene identified a novel substitution, 2834A>T, in exon 18, changing the p.His945Leu amino acid. In silico analysis using PolyPhen-2 (http://genetics.bwh.hardvard.edu/pph2/) predicted that this change is probably damaging, with a score of 1.0 (0-1).

Tau/α‐synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study

Background: No CSF or plasma biomarker has been validated for diagnosis or progression of PD.

Subacute progressive aphasia: a rare presentation of Creutzfeldt-Jakob disease.

A 66-year-old previously healthy man came to our hospital because of subacute cognitive impairment. The patient had begun with language and memory disturbances 1 month earlier. The cognitive exam revealed a severe impairment of speech fluency, frequent phonemic paraphasias and moderate difficulties in repetition and naming. Comprehension and reading were initially preserved, while episodic memory was moderately impaired. No extrapyramidal, cerebellar, or any other alteration was found in the neurological exam. Initial evaluation, which included biochemical, microbiological and immunological analyses, as well as a brain CT scan were all normal. Cerebrospinal fluid (CSF) examination, including 14.3.3 protein, revealed no abnormalities. After excluding infective, metabolic and other secondary causes, further investigations were considered. An encephalogram showed focal low voltage, fast rhythmic activity arising from the left parietal lobe (Fig. 1a, asterisks). With a working diagnosis of epileptic pseudodementia, the patient was initially treated with oxcarbazepine, with no cognitive improvement. In view of the encephalogram results, a cranial-MRI was performed 5 days after admission looking for a structural lesion. MRI demonstrated a predominant left cortical atrophy, mainly located at frontotemporal lobes, together with restricted diffusion at the left hemispheric cortex, which were considered as consistent with Creutzfeldt–Jakob disease (CJD) (Fig. 1c, d). In the following days, a Tc99m-HMPAOSPECT revealed a marked diffuse hypoperfusion of the left hemisphere (Fig. 1e). A new encephalogram repeated 1 month later demonstrated periodic sharp wave complexes involving the entire left hemisphere (Fig. 1b). Regarding the cognitive domain, the patient rapidly deteriorated, loosing the ability to communicate (mutism and very severe comprehension impairments) in less than 2 months. In the following months, his condition continued worsening and he died 5 months after the symptoms onset (Table 1). Necropsy demonstrated spongiform changes, neuronal loss and cortical accumulation of prion protein, mainly in the left hemisphere, confirming the diagnosis of CJD. Histology was very suggestive of the MM2-variant, although molecular analysis could not be done. Rapidly progressive dementias (RPDs) are neurological conditions that characteristically develop over weeks to months. In contrast to most dementing conditions, RPD can be quickly fatal. Therefore, a prompt evaluation is critical, especially looking for some treatable conditions. Among RPDs, CJD represents the most common cause (annual incidence of 1 per 1,000,000 population) [1]. Most cases of CJD exhibit a characteristic clinical course consisting of rapid cognitive decline, myoclonus, usually associated with encephalogram abnormalities and CSF elevation of 14.3.3 protein, and a rapid fatal course [2]. However, there are also atypical variants, commonly associated to longer survivals, which manifest with unusual clinical features that may complicate the correct diagnosis [3, 4]. Although 14.3.3 protein and encephalogram are important diagnostic tools for CJD, they have characteristically lower sensitivity & Javier Riancho javier.riancho86@gmail.com

The Relationship Between Atrophy and Hypometabolism: Is It Regionally Dependent in Dementias?

Neuronal failure leading to dementia in neurodegenerative diseases is evidenced in vivo by functional and structural changes in the brain such as reductions of glucose consumption and volume of grey matter. The earliest phase of cognitive decline and presymptomatic stages of these diseases are heralded by specific patterns of hypometabolism, even in the absence of atrophy, which are currently considered as diagnostic biomarkers. Atrophy is less consistently found as an initial marker of these diseases and is invariably present in moderate to severe stages with a disease-related topography. The relationship between these two markers is not uniform, but in the two diseases in which they have been directly compared, Alzheimer’s and Parkinson’s disease, altered hypometabolism precedes and exceeds atrophy in most regions. This suggests a two-step degenerative process. In contrast to these findings, the hippocampus skips this pattern and is more structurally than functionally affected, thereby suggesting a different pathological mechanism in this particular area. More studies are needed to disentangle the mechanisms underlying both markers and their relationship in neurodegenerative diseases.

Nonanaplastic pleomorphic xanthoastrocytoma with meningeal dissemination presenting with bilateral visual loss.

Pleomorphic xanthoastrocytoma (PXA) is a brain neoplasm included in the astrocytic group, exceptionally manifesting with meningeal dissemination. We described a 27‐year‐old patient presented with acute bilateral visual loss and papilledema with normal brain computed tomography scan, initially mimicking idiopathic intracranial hypertension (IIH). Brain and spinal cord magnetic resonance imaging (MRI) study revealed a subtle area of hyperintensity of the gyri surrounding the left central sulcus, and contrast enhancement of the thoracic leptomeninges. Brain biopsy of the parietal lesion revealed nonanaplastic PXA. Treatment with temozolomide was given. Yearly control MRI demonstrated new brain lesions and marked progression of leptomeningeal spinal enhancement. In spite of this, the patient has remained stable with no new symptoms. Nonanaplastic PXA may present with widespread meningeal dissemination with acute visual loss and papilledema mimicking IIH, and no clinical progression at 3 years.

From ileostomy to sudden quadriplegia with electrocardiographic abnormalities: a short and unfortunate path.

Hyperkalemia is a rare cause of acute onset muscular weakness that must be rapidly recognized because it is potentially lethal if not treated [1]. We report on a case of sudden onset quadriplegia secondary to hyperkalemia with rapid improvement after treatment. A 60-year-old male presented to the emergency department with quadriplegia. One month before onset, he had undergone subtotal colectomy for polyposis followed by several immediate postoperative complications requiring ileostomy, which led to persistent diarrhea. Two hours earlier he had suddenly experienced impossibility to move his limbs and neck. He denied pain, numbness or shortness of breath. Blood pressure, heart rate, temperature and oximetry were all normal; no overt signs of dehydration were observed. On neurological examination the patient was conscious and orientated with flaccid quadriplegia and generalized areflexia (Supplementary material: video, segment 1). Cranial nerves were intact except for paralysis of the trapezius and sternocleidomastoid muscles. There was no sensory involvement. ECG findings are illustrated in Fig. 1a. Serum potassium was 10.4 mEql/L, sodium 125 mEq/L, magnesium 0.6 mg/dL, calcium 9.4 mg/dL, urea nitrogen 171 mg/dL, creatinine 4.9 mg/dL and creatin kinase 213 U/L. Arterial blood pH was 7.31 and serum bicarbonate 20.9 mmol/L. Treatment with furosemide, bicarbonate, calcium gluconate, insulin and glucose solution perfusion was started. After 30 min he noticed progressive recovery of strength, being asymptomatic 2 h later (Supplementary material: video, segment 2). ECG abnormalities disappeared within a few hours after admission (Fig. 1b). His past medical history included alcohol and tobacco abuse, diabetes mellitus, chronic pancreatitis, hypertension and ischemic heart disease. He was being treated with insulin, metformin, enalapril, acetylsalicylic acid, gabapentin and acetaminophen. The current paper describes the case of a patient presenting with sudden quadriplegia associated with secondary hyperkalemia [1]. Most cases of sudden or acute paralysis are due to structural lesions of the central or peripheral nervous system. Etiology of acute quadriplegia includes brainstem stroke or hemorrhage (usually accompanied by altered level of consciousness and cranial nerve involvement), cervical cord lesions, including trauma, disc herniation and infarction (pain in the neck and sensory involvement are characteristic), Guillain Barré syndrome (usually accompanied by low back pain and loss of tendon reflexes), botulism (typically preceded by nausea, vomiting, blurred vision and diplopia) and tick paralysis (caused by a neurotoxin secreted by ticks in endemic areas). It is also worth mentioning, as an exceptional cause for acute Electronic supplementary material The online version of this article (doi:10.1007/s10072-012-1221-8) contains supplementary material, which is available to authorized users.