Hereditary spastic paraplegia (HSP) is a group of genetic disorders caused by >80 genes that can be described as either pure or complex forms.We report a case of a patient with a complex form of SPG7 with significant cognitive impairment.A 42-year-old man presented with a 10-year history of dysarthria, 5 years of gait difficulties, and 3 years of cognitive symptoms. Neuropsychological analysis showed deficits involving speed of information processing, mental flexibility, ideational fluency, verbal concept formation, visual working memory, and visual-spatial perception. Next-generation sequencing on whole blood revealed 2 heterozygous pathogenic variants in SPG7 (c. 1049_1077del, p. Pro350Glnfs*36 and c. 1529C>T, p. Ala510Val).There are emerging reports of complex forms of SPG7 presenting with impairments in memory, executive dysfunction, language, visuospatial processing, social functioning, and emotional communication. In this report, we describe a complex SPG7 patient who underwent formal neuropsychological testing to assess cognitive status in depth. This revealed deficits in speed of processing, visuospatial working memory and perception, impaired non-verbal intellect, and overall lack of insight, which have not yet been described in the literature.
Choroid plexus xanthogranulomas are rare, typically incidental intraventricular lesions that infrequently become symptomatic. When symptomatic, they most often present with headache or hydrocephalus, whereas cognitive sequelae and postoperative neuropsychological outcomes remain poorly characterized. A 63-year-old right-handed man with bilateral trigonal intraventricular lesions, larger on the right, presented with headaches and a history of subjective progressive memory complaints. He underwent resection of the right-sided lesion through a right temporoparietal approach. Immediately after surgery, he developed a severe and persistent amnestic-cognitive syndrome with profound inability to retain new information, confabulation, reduced insight, and marked remote-memory disturbance. Neuropsychological evaluation 3 months postoperatively demonstrated severe anterograde impairment in verbal learning and delayed visuospatial recall, together with substantial retrograde memory impairment involving autobiographical episodic recollection, personal semantic memory, and public semantic knowledge. This case suggests that bilateral trigonal xanthogranulomas and their surgical treatment may place distributed memory networks at substantial risk. Because formal preoperative neuropsychological testing and direct review of the original preoperative MRI were unavailable, the relative contributions of preexisting bilateral disease burden and postoperative network disruption cannot be fully separated. The case supports broader baseline cognitive assessment, precise laterality-specific surgical description, and structured postoperative neuropsychological follow-up for lesions near posterior medial and limbic white-matter pathways.
Alexander disease (AxD) is a rare progressive astrogliopathy and leukodystrophy caused by heterozygous pathogenic variants in the gene encoding glial fibrillary acidic protein (GFAP). Cognitive problems in AxD have long been recognized, but domain-specific neuropsychological descriptions of adult-onset Alexander disease (AO-AxD) remain sparse. We report a genetically confirmed 53-year-old man with AO-AxD who underwent comprehensive neuropsychological assessment because of progressive cognitive and behavioral complaints. The profile was characterized by deficient verbal episodic memory retrieval and reduced set-shifting efficiency, with relatively preserved recognition memory, language, visuospatial abilities, and most attentional measures. Structural MRI showed characteristic medullary and upper cervical cord involvement but only limited supratentorial white matter abnormalities. To contextualize the case, we reviewed published AO-AxD reports with domain-specific neuropsychological testing. The available literature remains limited and heterogeneous, but suggests that cognitive manifestations in AO-AxD may include retrieval-based memory deficits, executive inefficiency, and visuospatial difficulties. We discuss these findings in relation to white matter dementia, fronto-subcortical and fronto-hippocampal network dysfunction, and potential astrocyte-mediated mechanisms.
Amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E) and with hemorrhage (ARIA-H) are common adverse effects of amyloid-targeting therapies (ATT), characterized on MRI by T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities and susceptibility-sensitive hypointensities, respectively. ARIA resulting from ATT is not commonly associated with reduced diffusion or acute infarcts. In this case series, we describe three patients with mild cognitive impairment due to Alzheimer's disease (AD) - a 75-year-old woman, a 74-year-old woman, and an 80-year-old man (APOE ε3/ε3, ε4/ε4, and ε3/ε4, respectively) - who developed ARIA accompanied by transient foci of reduced diffusion within the first six months of donanemab treatment, without permanent T2/FLAIR correlates. The diffusion-restricting lesions may represent ischemic infarcts, although the lack of permanent T2/FLAIR correlate is atypical. Clinicians should be aware that reduced diffusion may accompany ARIA. The course can be highly dynamic, and both the clinical presentation and management implications may vary.
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by progressive dementia and multiple bone cysts. The known pathogenic genes include TYRO protein tyrosine kinase binding protein (TYROBP) on chromosome 19q13.1 and triggering receptor expressed on myeloid cells 2 (TREM2) on chromosome 6p21.1. Until now, no case related to TYROBP gene mutation has been reported in the Chinese population. We report a 39-year-old Chinese Han patient who presented with early-onset dementia and cystic bone lesions. Brain magnetic resonance imaging showed extensive cerebral atrophy with ventricular enlargement and diffuse, symmetric white matter lesions. Whole-exome sequencing identified a nonsense mutation, c.214C > T (p.Arg72Ter), in the TYROBP gene. Minigene experiments suggested that this variant may partially affect TYROBP splicing, providing supplementary transcript-level evidence for NHD. This is the first genetically confirmed case of NHD associated with a homozygous TYROBP c.214C > T (p.Arg72Ter) variant in the Chinese population. Our findings expand the mutation spectrum of NHD and provide new reference evidence for its molecular diagnosis and genetic counseling.
Language lateralization (LL) is a key aspect for preoperative surgical planning in patients with brain tumors. Crossed cerebro-cerebellar (CCC) activation, derived from functional magnetic resonance imaging (fMRI), guides LL determination. Structural features, such as gray matter volume (GMV), may provide complementary information on structural asymmetries associated with LL. However, the literature suggests that LL may change after surgery, and less is known about its variation over repeated surgeries. This case study aims to characterize LL in a patient with a recurrent glioma using both functional and structural measures. The case is a 33-year-old woman who underwent three intraoperative awake speech mapping tumor resections. Conventional MRI and fMRI were acquired before each surgery: 2017 (T1), 2020 (T2), and 2023 (T3). CCC activation was used as a functional marker of LL, and GMV was used to examine structural asymmetries. Linguistic and cognitive functions were examined pre-and postoperatively. Although supratentorial activation patterns showed some variability, CCC activation consistently indicated left-hemisphere LL. Structural analyses revealed differential volumetric patterns between the ipsilateral and contralateral language regions. Combining functional and structural measures, such as CCC activation and GMV analysis, may provide complementary information for assessing LL in patients undergoing repeated surgeries.
Partial locked-in syndrome (PLIS) is a rare stroke presentation in which preserved consciousness is masked by severe motor impairment, potentially leading to misinterpretation as encephalopathy. We report a patient in her early seventies with vascular risk factors and a prior pontine infarct who presented with acute quadriplegia and mutism. Initial clinical impressions raised concern for altered mental status. However, subsequent neurological examination demonstrated preserved awareness, with consistent eye tracking and command following through head movements. Examination showed bifacial and bulbar weakness, severe dysarthria, and minimal right arm movement. MRI demonstrated new infarcts in the left cerebral peduncle, posterior limb of the internal capsule, thalamus, and temporal lobe, superimposed on a prior pontine lesion. This distributed but strategically located pattern of injury affected bilateral corticospinal pathways and explained the profound motor impairment despite preserved consciousness. This case highlights how PLIS may mimic encephalopathy in the acute care setting and underscores the importance of structured bedside assessment for detecting preserved awareness in mute or immobile patients. Early recognition has implications for airway management, stroke evaluation, communication strategies, and prognostic counseling.
There are few reports describing the coexistence of alien hand syndrome (AHS) and crossed aphasia. The patient was a right-handed woman in her seventies. Following an infarction involving the medial right frontal lobe and the genu of the corpus callosum, she developed groping, grasping, and intermanual conflict (IC) in the left hand, along with crossed aphasia. The groping and grasping may have resulted from impaired inhibition due to supplementary motor area damage, whereas IC may have arisen from disrupted interhemispheric information transfer. The absence of apraxia in the right hand and the presence of IC in the left hand suggested that praxis functions were lateralized to the left hemisphere. The symptoms of crossed aphasia resembled those typically observed after left hemisphere damage, raising the possibility that language function was lateralized to the right hemisphere. The AHS symptoms in the left hand were considered to have resulted from different mechanisms, while the aphasia may have emerged due to atypical lateralization of language.
Involuntary mirror movements (MMs) may occur in the nonparetic hand after stroke events, accompanying voluntary movements of the paretic hand. These can interfere with unimanual dexterity and bimanual coordination, potentially impacting the performance of activities of daily living (ADLs). However, neither the changes in such MMs over time nor effective interventions for them have been sufficiently established. We recently treated a patient with right putaminal hemorrhage following a stroke, who presented with difficulties performing bimanual tasks (e.g. typing and washing hair) because of prominent MMs in the nonparetic hand accompanying movements in the paretic hand, despite mild upper-limb motor paralysis and ADL independence. To facilitate voluntary paretic hand movement while targeting independent control of both hands, we implemented a bimanual asymmetric exercises (BAEs), wherein the patient performed different motor tasks with each hand concurrently. This reduced the patient's MMs while improving bimanual coordination. Even when paretic upper-limb impairment is mild, and patients can perform ADLs independently, evaluations and interventions should be conducted, while remaining mindful that MMs in the nonparetic hand can reduce overall upper-limb performance. BAEs may represent an effective approach for reducing MMs.
Direct electrical stimulation (DES) during awake craniotomy is the gold-standard for language mapping; however, conventional tasks (e.g. counting, object naming, reading) provide limited sensitivity to grammatical and sentence-level processes. The present study introduces the first intraoperative application of the English Verb and Noun Test for Perioperative testing (VAN-POP), a sentence-based paradigm designed to probe object and action naming with finite verbs in past and present tense. VAN-POP was administered to four UK English-speaking patients undergoing awake craniotomy for WHO grade II-III gliomas involving frontal, temporal, or parietal regions. Language-positive sites were identified in three patients, and real-time monitoring revealed language disruptions in three patients. DES elicited action naming disruptions in two patients. Middle and inferior frontal stimulation induced tense errors and verbal-visual paraphasias, whilst angular gyrus stimulation induced speech arrest. During resection, three patients exhibited action naming disruptions, including semantic and morphosyntactic errors, anomia, and delays. Postoperatively, no patients showed clinically significant deficits requiring speech and language therapy. These findings demonstrate that VAN-POP is feasible for intraoperative use and increases sensitivity to grammar-related cortical sites beyond conventional mapping approaches. Incorporating finite verb production within DES protocols may improve delineation of language networks, supporting better preservation of function.
Opsoclonus myoclonus syndrome (OMS) is a rare inflammatory disease of the central nervous system characterized by ocular movements, ataxia, irritability, myoclonus, and sleep disturbances and is thought to result from variable etiologies. We report a case of OMS following severe malaria in a patient living with Human Immunodeficiency Virus (HIV). This is a 47-year-old woman, known to be HIV-positive, for the past 6 years, and on highly active antiretroviral therapy (HAART) with Tenofovir-Lamivudine-Atazanavir, to which she is strictly compliant. Her last viral load was undetectable. Two weeks after being treated for severe malaria due to Plasmodium falciparum, the patient presented with multidirectional ocular saccades associated with trunk myoclonus. This was subsequently followed by aggressive behavior sleep disturbances, and severe ataxia. The diagnosis of post-infectious opsoclonus-myoclonus was made after ruling out an HIV-related central nervous system (CNS) infection and a paraneoplastic origin. Initial management consisted of high doses of intravenous (IV) methylprednisolone which resulted in partial improvement of the symptoms. The subsequent addition of rituximab led to complete resolution of the symptoms and the restoration of functional autonomy. This case suggests a possible relationship between malaria and OMS in the context of HIV infection and highlights the potential benefit of an IV corticosteroid and rituximab combination therapy as a substitute for IV immunoglobulins in resource-limited settings.
Joubert Syndrome (JS) is a rare neurodevelopmental disorder characterized by cerebellar ataxia, oculomotor apraxia, and the characteristic "molar tooth sign" on brain MRI. Niemann - Pick Disease Type C (NPC) is an autosomal recessive lysosomal storage disorder associated with progressive neurological involvement, including ataxia and vertical supranuclear gaze palsy. Although these disorders have distinct genetic and pathophysiological mechanisms, they share overlapping clinical features such as ataxia, oculomotor abnormalities, and developmental delay, which may complicate the diagnostic process. We evaluated a 7-year-old Afghan girl with speech impairment and neuromotor developmental delay. Neurological and radiological assessments were conducted, followed by genetic analysis using next-generation sequencing to explore underlying mutations. Neurological examination revealed cerebellar ataxia, oculomotor apraxia, and dysmetria, consistent with JS. Brain MRI demonstrated the characteristic molar tooth sign. Genetic testing identified homozygous mutations in the NPC1 gene (c.1123A > G, p.Thr375Ala) and the AHI1 gene (c.2671C > T, p.R891). Despite the NPC1 mutation, no classical signs of NPC - such as vertical gaze palsy or clinical deterioration - were observed. Family history revealed a bedridden cousin, though no diagnostic information was available. Based on genetic findings, miglustat therapy was initiated. This case illustrates the diagnostic challenges arising from coexisting pathogenic mutations in genes associated with different neurological syndromes. Although clinical features primarily aligned with Joubert Syndrome, the possibility of subclinical or emerging Niemann-Pick Disease Type C could not be excluded. Genetic overlap emphasizes the importance of integrated clinical and molecular evaluation in rare neurogenetic disorders.
The ability to recognize and anticipate potential danger is crucial for survival across species. The midbrain periaqueductal gray (PAG) is implicated in regulating threat-anticipatory responses, including heart rate deceleration (threat bradycardia) which is typically observed during freezing. Although animal studies have provided causal evidence that the PAG regulates threat-anticipatory bradycardia, causal evidence does not exist in humans. To address this translational gap, we performed a single-case study to elucidate the causal role of the human PAG in threat-anticipatory bradycardia using deep brain stimulation (DBS). We report on a participant who received PAG DBS for chronic pain treatment. The participant performed an instructed fear task during which cues were presented signaling either threat of electrical shock or safety. During the task, we applied DBS in the PAG, no DBS, or DBS at a control site bordering the PAG. Deep brain stimulation in the PAG significantly increased threat bradycardia responses (i.e. reduced heart rate for threat vs. safety) compared to no stimulation, whereas control-site stimulation bordering the PAG did not significantly affect threat bradycardia. Together, this single-case report provides causal evidence that the human PAG regulates threat bradycardia responses, furthering our understanding of the neural circuit underlying defensive reactions in humans.
Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited disorders primarily characterized by progressive spasticity and lower extremity weakness. Traditionally associated with corticospinal tract dysfunction, HSP was long presumed to leave cognitive function largely unaffected. However, growing evidence increasingly recognizes cognitive impairment as a relevant feature of the condition. The primary aim of this study is to broaden the understanding of the cognitive profile in HSP, by examining cognitive impairments in a Greek cohort. A detailed neuropsychological assessment was conducted in 10 HSP patients and 30 healthy controls, including measures of executive function, memory, attention, processing speed, visual scanning, and social cognition. Our findings revealed widespread cognitive impairment, with prominent deficits in processing speed, attention, visual scanning, and social cognition, supporting reduced cognitive resilience in HSP. On a neuroanatomic level, the observed cognitive decline in HSP may indicate localized dysfunction within the frontal area of the brain among affected patients. We futher hypothesize that genetically distinct HSP subtypes converge on shared cellular disruptions that may compromise frontotemporal networks, thereby producing similar cognitive phenotypes.
SNCA gene duplications are a rare cause of autosomal dominant Parkinson's disease (PD), linked to early onset and cognitive or behavioral symptoms. Data from Turkey remain limited. To describe the clinical, cognitive, behavioral, and genetic features of three Turkish sisters with familial PD due to SNCA duplication. This retrospective case series includes three sisters with PD. Clinical history, neurological examinations, Unified Parkinson's Disease Rating Scale (UPDRS-III) scores, treatment history, and neuropsychological findings were recorded. Genetic testing was conducted using whole exome sequencing. One sister underwent subthalamic nucleus deep brain stimulation (STN-DBS), and outcomes were followed over time. All patients presented with early-onset PD and classic motor symptoms, including bradykinesia and rigidity. Non-motor features such as REM sleep behavior disorder, orthostatic hypotension, urinary incontinence, and hallucinations were common. Two developed impulse control disorders, including hypersexuality and compulsive behaviors. Cognitive decline occurred in two, with MoCA scores of 24 and 22, and neuropsychological testing revealed frontal and temporolimbic dysfunction. The sister treated with DBS showed initial improvement but later motor and cognitive progression. This first detailed Turkish familial series highlights the broad symptom spectrum of SNCA duplication PD and underscores the need for genetic and neuropsychiatric assessment in familial cases.
Primary progressive aphasia (PPA) refers to a group of clinically and pathologically heterogeneous syndromes characterized by progressive and relatively selective impairment in speech and language as the main cognitive domain in the early disease stage. The main clinical variants of PPA based on current diagnostic criteria include logopenic variant PPA (lvPPA), nonfluent variant PPA (nfvPPA), and semantic variant PPA (svPPA). Identification of speech/language and non-language abilities and in vivo biomarkers (such as neuroimaging, genetic, and biofluid studies) facilitates the correct classification of the main variants. PPA variants clinical presentation may overlap leading to a diagnosis of mixed or unclassified PPA. We report the case of a trilingual patient with a 10-year history of word-finding difficulties initially attributed to chronic alcohol abuse. Her clinical presentation was evocative of lvPPA with features of svPPA, while her neuropsychological testing and MRI data were suggestive of a diagnosis of svPPA. While β-amyloid PET brain imaging was negative, postmortem immunohistochemical analysis of the brain showed unequivocal evidence of Alzheimer's disease. We describe this case of complex PPA for which clinical data outperformed imaging biomarkers in predicting the underlying neuropathology and discuss chronic alcohol abuse as a potential risk factor for neurodegeneration.
CSF1R-related disorder (CSF1R-RD) is a rare neurodegenerative disorder linked to mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. Over 200 mutations and diverse clinicoradiographic phenotypes have been described thus far. This case series presents three patients with two CSF1R mutations (I827N and S840C) of which the S840C mutation is novel. We detail their clinical presentations, diagnostic evaluations, and the autopsy findings for one case associated with the I827N mutation, offering new insights into the pathology of this disease.
This case report presents the clinical evolution of a patient who developed delayed-onset parkinsonism and cognitive deficits following carbon monoxide poisoning (COP). After a symptom-free interval of approximately one month, the patient exhibited progressive neurological and cognitive impairments that significantly interfered with daily and occupational functioning. A combined therapeutic approach was implemented, involving pharmacological treatment, cycles of hyperbaric oxygen therapy (HBOT) and a tailored neuropsychological rehabilitation program. Longitudinal assessments documented progressive improvements, particularly in sustained attention, memory, and executive functioning, although residual difficulties persisted. This case highlights the relevance of individualized neuropsychological interventions in conjunction with medical treatment in facilitating functional recovery in patients with delayed neurological sequelae after COP.
A 69-year-old Japanese man presented with prosopagnosia, visual form agnosia for line drawings of objects, as well as alexia and agraphia for Kanji after infarction in the right fusiform gyrus and occipitotemporal lobe. In contrast, the verbalization of real objects and line drawings of actions was good. Visual recognition disorders that affect the identification of faces, line drawings, and Kanji suggest impaired processing related to multielement integration. Real objects and line drawings of actions, which are easy to process as visual units and tend to evoke kinesthetic images, were less affected after damage in the right occipital-inferior temporal pathway, suggesting that cognitive processing is possible via the dorsal pathway.
