Visual hallucinations.

Visual hallucinations have intrigued neurologists and physicians for generations due to patients' vivid and fascinating descriptions. They are most commonly associated with Parkinson's disease and dementia with Lewy bodies, but also occur in people with visual loss, where they are known as Charles Bonnet syndrome. More rarely, they can develop in other neurological conditions, such as thalamic or midbrain lesions, when they are known as peduncular hallucinosis. This review considers the mechanisms underlying visual hallucinations across diagnoses, including visual loss, network dysfunction across the brain and changes in neurotransmitters. We propose a framework to explain why visual hallucinations occur most commonly in Parkinson's disease and dementia with Lewy bodies, and discuss treatment approaches to visual hallucinations in these conditions.

Listening with intent.

Know how to listen and you will profit even from those who talk badly. Plutarch Listening in medicine is only of value when it is combined with an ability to decipher the patient's utterances and gestures and act upon them.

Earworms-A Narrative Review of Infectious Music.

This Arts and Medicine feature reviews the clinical and neurophysiologic features of earworms, music fragments heard in the mind that repeat over and over as if jammed in playback mode.

Noticing in neurology.

There are three classes of people: those who see, those who see when they are shown, those who do not see Leonardo da Vinci The three cardinal qualities necessary for the ideal neurologist are observation, the ability to reason backwards inferentially and specialist knowledge. Modern medical technology has greatly increased the ability to diagnose and treat disease but it has also encouraged a benign variant of abulia, which is killing off the art and science of clinical reasoning. Intent gazing at the unfamiliar with old eyes or a long look at the familiar with new eyes offers the neurologist an opportunity to discover hitherto unnoticed diagnostic signs far beyond the resolution of the brain scanner and even the light microscope. While there may be nothing new under the sun, there are plenty of old things that no one has observed, which have the potential to greatly improve clinical practice.

A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes.

BACKGROUND: Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). OBJECTIVE: To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia. METHODS: A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), ß-amyloid 1-42 (Aß42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and ß (soluble amyloid precursor protein (sAPP)α, sAPPß) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used. RESULTS: CSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls. CONCLUSIONS: A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies.

Neuropathological features of multiple system atrophy with cognitive impairment.

Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA-related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's-related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA-specific α-synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted.

Pantothenate kinase-associated neurodegeneration is not a synucleinopathy.

AIMS: Mutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase-associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases. METHODS: All three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations. RESULTS: All cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α-synuclein accumulation was detected in any of our PKAN cases. In one case (20-year-old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case. CONCLUSIONS: These findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.

High resolution MR anatomy of the subthalamic nucleus: imaging at 9.4 T with histological validation.

Using conventional MRI the subthalamic nucleus (STN) is not clearly defined. Our objective was to define the anatomy of the STN using 9.4 T MRI of post mortem tissue with histological validation. Spin-echo (SE) and 3D gradient-echo (GE) images were obtained at 9.4 T in 8 post mortem tissue blocks and compared directly with corresponding histological slides prepared with Luxol Fast Blue/Cresyl Violet (LFB/CV) in 4 cases and Perl stain in 3. The variability of the STN anatomy was studied using internal reference points. The anatomy of the STN and surrounding structures was demonstrated in all three anatomical planes using 9.4 T MR images in concordance with LFB/CV stained histological sections. Signal hypointensity was seen in 6/8 cases in the anterior and medial STN that corresponded with regions of more intense Perl staining. There was significant variability in the volume, shape and location of the borders of the STN. Using 9.4 T MRI, the internal signal characteristics and borders of the STN are clearly defined and significant anatomical variability is apparent. Direct visualisation of the STN is possible using high field MRI and this is particularly relevant, given its anatomical variability, for planning deep brain stimulation.

The neuropathology, pathophysiology and genetics of multiple system atrophy.

Multiple system atrophy (MSA) is an unrelenting, sporadic, adult-onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. MSA is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies, due to the presence of abnormal α-synuclein positive cytoplasmic inclusions in oligodendrocytes, termed glial cytoplasmic inclusions. These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α-synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA.

LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study.

AIMS: Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have been established as a common genetic cause of Parkinson's disease (PD). The distribution of LRRK2 mRNA and protein in the human brain has previously been described, although it has not been reported in PD cases with the common LRRK2 G2019S mutation. METHODS: To further elucidate the role of LRRK2 in PD, we determined the localization of LRRK2 mRNA and protein in post-mortem brain tissue from control, idiopathic PD (IPD) and G2019S positive PD cases. RESULTS: Widespread neuronal expression of LRRK2 mRNA and protein was recorded and no difference was observed in the morphological localization of LRRK2 mRNA or protein between control, IPD and G2019S positive PD cases. Using quantitative real-time polymerase chain reaction, we demonstrated that there is no regional variation in LRRK2 mRNA in normal human brain, but we have identified differential expression of LRRK2 mRNA with significant reductions recorded in limbic and neocortical regions of IPD cases compared with controls. Semi-quantitative analysis of LRRK2 immunohistochemical staining demonstrated regional variation in staining intensity, with weak LRRK2 immunoreactivity consistently recorded in the striatum and substantia nigra. No clear differences were identified in LRRK2 immunoreactivity between control, IPD and G2019S positive PD cases. LRRK2 protein was identified in a small proportion of Lewy bodies. CONCLUSIONS: Our data suggest that widespread dysregulation of LRRK2 mRNA expression may contribute to the pathogenesis of IPD.

A film of patients with movement disorders made in Queen Square, London in the Mid-1920s by Samuel Alexander Kinnier Wilson.

BACKGROUND: Through Edward Reynolds' collaboration with Samuel Alexander Kinnier Wilson's (SAKW) son, James, on Babylonian neurology and psychiatry, and his contact with James' nephew, Jim, grandson of SAKW, a remarkable film of patients with movement disorders, made by SAKW in the mid-1920s, has come to light. METHODS/RESULTS: The 20-min silent film with captions by SAKW includes patients with senile tremor, Parkinson's disease and postencephalitic parkinsonism, hemiballismus, Huntington's chorea, Sydenham's chorea, hysterical palsy and tremor, multiple sclerosis, and progressive lenticular degeneration. Most of the patients are filmed in the square outside the National Hospital. The British Film Institute dates the film to 1924 and the captions to 1925. The case records of 6 of the 14 patients, who were admitted to the National Hospital, Queen Square, under the care of Dr. SAKW have been identified and summarized. DISCUSSION: SAKW may have been stimulated and facilitated to make this film through his personal contact with Charlie Chaplin with whom he stayed at his Californian estate, probably in the summer of 1924. The first films of neurological patients were made in Europe and USA at the beginning of the 20th century, although most have perished. This may be one of the oldest examples from UK. It is also notable for the inclusion of Wilson's disease and a brief shot of SAKW himself.

The motor prodromes of parkinson's disease: from bedside observation to large-scale application.

There is sufficient evidence that the pathological process that causes Parkinson's disease begins years before the clinical diagnosis is made. Over the last 15 years, there has been much interest in the existence of a prodrome in some patients, with a particular focus on non-motor symptoms such as reduced sense of smell, REM-sleep disorder, depression, and constipation. Given that the diagnostic criteria for Parkinson's disease depends on the presence of bradykinesia, it is somewhat surprising that there has been much less research into the possibility of subtle motor dysfunction as a pre-diagnostic pointer. This review will focus on early motor features and provide some advice on how to detect and measure them.

A clinico-pathological study of subtypes in Parkinson's disease.

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25%), tremor dominant (31%), non-tremor dominant (36%) and rapid disease progression without dementia (8%) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70% of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.

Changes in psychomotor effects of L-dopa and methylphenidate after sustained dopaminergic therapy in Parkinson's disease.

BACKGROUND: Sustained drug therapy in Parkinson's disease may alter the psychomotor responses to acute challenges with dopaminergic drugs, L-dopa and methylphenidate, and cause cross sensitisation. METHODS: The mood, psychomotor and reward potentiating effects of an acute challenge with L-dopa and methylphenidate on separate occasions were assessed under double blind (medication naïve) conditions after a placebo and then the testing sessions were repeated in the same (medication experienced) patients following a median period of 16.7 months of continuous dopaminergic drug therapy. RESULTS: In the medication naïve condition, affect was not changed by L-dopa or methylphenidate and only L-dopa improved motor function. In the medication experienced condition, active drugs improved positive affect compared with the medication naïve condition and there was an enhanced effect of L-dopa on motor function. Reward responsivity was enhanced by both L-dopa and methylphenidate in medication naïve and experienced conditions. CONCLUSION: Sustained dopaminergic drug therapy augments the motor effects of an acute challenge with L-dopa and induces euphoriant effects to L-dopa and methylphenidate challenges.

Olfaction in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDDs).

BACKGROUND: Positron emission tomography and single photon emission computed tomography scanning have 87-94% sensitivity and 80-100% specificity to differentiate patients with Parkinson's disease (PD) from control subjects and patients with essential (ET) or atypical tremor. More than 10% of patients diagnosed as early PD can have scans without evidence of dopaminergic deficiency (SWEDDs). This study investigated whether smell tests can help identify possible cases with SWEDDs. METHODS: The 40 item University of Pennsylvania Smell Test (UPSIT) was used to evaluate the sense of smell in 21 SWEDDs patients. Twenty-six ET patients, 16 patients with a diagnosis of idiopathic adult onset dystonia (D), 191 non-demented PD patients and 136 control subjects were also tested. Multiple regression analyses were used to compare the mean UPSIT score in the SWEDDs group with the other four groups (ET, D, PD and controls) after adjusting for the effects of relevant covariates. RESULTS: The mean UPSIT score for the SWEDDs group was greater than in the PD group (p<0.001) and not different from the mean UPSIT in the control (p = 0.7), ET (p = 0.4) or D (p = 0.9) groups. Smell tests indicated a high probability of PD in only 23.8% of SWEDDs as opposed to 85.3% of PD patients. CONCLUSIONS: In a patient with suspected PD, a high PD probability on smell testing favours the diagnosis of PD, and a low PD probability strengthens the indication for dopamine transporter imaging.