INTRODUCTION
The term neuro - referring the cells of brain /neurons, Degeneration- deterioration and loss of function in the cells of a tissue or organ.
These disorders are an umbrella term for a spectrum of diseases that can cause symptoms ranging from mood disturbances to dementia, involuntary movements, and cognitive decline that affect daily life.
The lack of clear criteria for defining neurodegenerative disorders means that there is a wide variety of etiologies and pathophysiology to understand the clinical, pathological, molecular pathways, and therapeutic targets in management. This creates a broad scope for future research and treatment advancements.
This can make it challenging to diagnose and treat these diseases effectively. However, researchers are working to better understand the underlying mechanisms of neurodegenerative disorders, which could lead to more effective treatments in the future.
Neurodegenerative disorders can impact many different facets of functioning, from basic tasks like walking and eating to more complex tasks like memory, language, and problem-solving. These diseases can cause significant impairments in daily life, and they can be challenging for individuals and their families to manage.
With the preliminary knowledge of neurodegeneration meaning the neuronal death through various processes with the emphasis mainly placed on the few diseases like Alzheimer's, Parkinsons ,huntingtons ..
Lack of demarcation and absolute criteria for defining neurodegenerative disorders is creating grey zone of overlap between various diseases like amyloid in Alzheimer's and stroke, and presence of mixed disorders like Alzheimer's and Parkinson's.
Some zones of neurodegenerative disorders remain unexplored despite being debilitating like other disorders.
This article serves as the educative and practical tool for delving into the depths of the neurodegenerative disorders and it's overlap with the other mimickers.
This article helps in broadening our concepts of the classification of neurodegenerative disorders.
This article emphasizes mainly on the practical case-based approach and their diagnostic and therapeutic uncertainties and their associations with neuronal degeneration.
This article also provides with the practical approaches and the follow up of the cases through our platforms like PaJR, CBBLE, UDHC, with the pros and cons of these platforms also being discussed.
Overall, managing neurodegenerative disorders requires a comprehensive and individualized approach that takes into account the unique needs and challenges of each patient.
Neurodegenerative disorders are a major public health and medical problem that impose substantial damage on people all over the world. The rate and frequency of these diseases increase significantly with age; consequently, the prevalence is anticipated to rise in the near future as life expectancies in many countries keep increasing.(Checkoway et al., 2011) Apart from the selective static neuronal loss seen in metabolic or toxic illnesses, the gradual loss of selectively susceptible neuronal populations characterises neurodegenerative disorders.(Dugger & Dickson, 2017) Pyramidal and extrapyramidal movement disorders, as well as cognitive or behavioural disorders, are the most prevalent clinical manifestations of neurodegenerative diseases. Few patients exhibit clear syndromes, while the majority have complex clinical characteristics.
Medical cognition tools, such as Patients Journey Recording System(PaJR), User Driven Health Care(UDHC), and Case Based Blended Learning Ecosystems (CBBLE) are playing a predominant role in resolving the clinical complexity(diagnostic and therapeutic uncertainty) of different neurodegenerative diseases. Tools like
synchronous face-to-face encounters and asynchronous communication and learning across numerous stakeholders in connected online space (UDHC, PaJR) are frequently utilised through different medical cognitive platforms and blended to construct CBBLE.(Biswas R, 2022b)
Some of the hallmarks of clinical complexity are the presence of ambiguity, non- linearity, and unpredictability while also exhibiting an overarching pattern that, with time, resolves itself via attractor states.(Plsek & Greenhalgh, 2001). As physician attractors, we are especially privileged to "be" with our patients regardless of their diagnosis. This is the only way we can know the outcomes of our patients, where our "being" with them is the most substantial and often
disregarded intervention.(Biswas R, 2022b)
User Driven Healthcare (UDHC) is a subclass of "Medical Cognition" in which numerous users, all healthcare stakeholders, including patients, interact online to comprehend and make decisions regarding meeting patient needs.(Purkayastha et al., 2015) This paper conceptualises coordinated patient care through the perspective of engaged stakeholders utilising information technology integration tools for digital infrastructures and also distinguish this paradigm from the ubiquitous conceptualization of dyadic relationships between clinician-patient, patient-nurse, and clinician-nurse, and provide the holistic integration of all stakeholder inputs, in the clinic and augmented by online communication in a multi- national context. Here, we will explore an illustration of user-driven health care (UDHC), a network of providers, patients, students, and researchers collaborating to improve neurodegenerative patient care. We will describe UDHC as well as its opportunities and challenges in care coordination to reduce costs, bring equity, and enhance care quality, and we'll also share relevant evidence in the field of neurodegenerative disease.
Case-based blended learning ecosystems (CBBLE) seek to provide a new perspective on accuracy-driven "ancient precision medicine" and to fortify the connection between ancient precision approaches and modern technology and omics-driven research.(Podder et al., 2018) Precision medicine is tailored, patient-specific care based on a patient's genetic makeup and medical records. This is crucial for optimising patient needs and outcomes, minimising harm to the healthcare ecosystem by limiting under- and overdiagnosis and treatment. At this juncture, CABBLE is the most important instrument for reducing under/overdiagnosis and under/overtreatment, as it is a practical method for doing so.
Patients Journey Recording System (PaJR), wherein the dyadic relationship between a single single patient and a doctor is transformed in order to provide a team of physicians for a single patient with comprehensive, patient-centered careElectronic records may only improve the accessibility to documentary evidence of incomplete assessment and inappropriate treatment, but they may not depict true quality of
healthcare that reflects respect for the patient, thorough follow-up and medical obligation for individual patients, and more in-depth research of the root causes of illness by teams of medical practitioners who have a professional relationship with the patient.(Biswas R, 2022a) In each of the PaJR groups, the patients are deidentified as well as anonymous, and the majority of them interact by sharing regular updates on the group as their own advocate without revealing their identity to the group. This ensures that no online traces of one‘s identification exist, and all members of the group take the uttermost precautions to protect the patient's privacy and thus the confidentiality is preserved with concern. To begin with, a trained students generate a de-identified, online-accessible patient case report as the initial step and before sharing as an open access case report, the patient would verify the anonymity of all details in the case report. To proceed with this, the patient's signed informed consent form is obtained. It is intended for patients to take command of their own recovery and become more knowledgeable about the science behind their illness journey.
The aforementioned cognitive tools contribute not only to resolving clinical complexity, but also to enhancing the clinical knowledge of health professionals through collective conversational learning on these platforms. Here, we present several of our neurodegenerative cases and illustrate how the these medical cognition tools are greatly influencing the optimisation of clinical complexity and uncertainty.
CASE PRESENTATIONS
CASE 1
51-year-old male farmer presented with swelling of left foot and loss of sensations over left foot for 3years, ulceration over sole for 11 months. On further probing patient reported having sustained injury over left foot 25years back another episode 3years back and had fracture of base of 5th metatarsal and was managed conservatively patient continued to limp post trauma and developed tingling and numbness over his left foot with progressive loss of sensations associated with slippage of footwear affecting his daily routine. Examination revealed 51M with intact higher mental functions, normal cranial nerve examination motor examination of left lower limb revealed absence of dorsiflexion and eversion of foot and great toe extension with all deep tendon reflexes present, sensory showed absence of all sensory modalities below ankle, palpable common peroneal nerve with high steppage gait and provisionally diagnosed as Diffuse sensory motor axonal mononeuropathy of the Sciatic nerve with our differentials as? Hansen's? nerve sheath tumor.
HRUS-long segmental focal fusiform enlargement of sciatic nerve extending to common peroneal and tibial nerve.
MRI-similar cystic lesions in tibial and common peroneal nerves? intraneural ganglion of tibial nerve? hamartoma? nerve sheath tumor?
NCV studies showed no response left tibial and common peroneal nerve and superficial peroneal nerve and sural nerve.
SSS showed no AFB.
Treatment - was given symptomatic treatment of tab gabapentin 100mg, tab Amitryptiline 25 mg. Patient is being followed up in the pajr group for further progression or relief of symptoms.
CASE 2
A 47-year schoolteacher came to the OPD with complaints of involuntary movements of upper and lower limbs for 4 years, followed by slurring of speech for 3 years, difficulty in swallowing and urinary incontinence for 2 years, Involuntary movements high amplitude, purposeless movements, progressive affecting his quality of sleep with no associated triggers and relieving factors seen. Patient on further questioning gave the history of similar complaints in the family - mother, sister, aunt. On examination - patient is conscious, coherent, cooperative with MMSE 26/30. Detailed examination of CNS revealed cranial nerves intact. Motor - normal bulk, power and reflexes ++, no sensory involvement, Cerebellum -no nystagmus, Rhomberg's slight swaying present. Initial differentials were Spinocerebellar ataxia and Huntington's disease.
GENETIC ANALYSIS for SCA and Huntington's revealed increased CAG repeats and negative for SCA and diagnosis of HUNTINGTONS CHOREA is made.
CASE 3
A 59-year-old female , company employee, presented with bilateral upper and lower limb weakness for 6 months. The weakness initially began in her left lower limb, it was insidious in onset and progressive in nature. She experienced frequent falls while carrying out her daily activities and experienced multiple injuries on her lower limbs. Gradually, she developed weakness in the left upper limb. She was able to carry out her daily activities with discomfort for 4 to 5 months, after which the weakness spread bilaterally to her right upper and lower limb. She was unable to maintain her balance or walk without support and required assistance to bathe or use the washroom. The patient was unable to raise her lower limbs from the bed in supine position and complained of neck pain radiating bilaterally to her upper limbs. On examination, the bulk and power of the muscles were reduced and deep tendon reflexes were exaggerated bilaterally in both upper and lower limbs.
There were no deficits in her cognition or memory, no dysarthria or loss of sensations, and her bowel and bladder movements were normal. Her Laboratory investigations revealed raised ESR (25mm/hr) and mild normocytic, normochromic anaemia. Liver function tests, Renal function tests, Thyroid profile and Vitamin D estimations were within normal ranges. MRI of the cervical spine revealed mild subarticular disc protrusions at C5-C6 levels, mild posterior central disc bulge at C3, C4, and spinal canal narrowing at C5-C6 and C6 -C7 levels. EMG study revealed decreased motor unit recruitment with low amplitude polyphasic MUAP and abnormal spontaneous activity–fasciculation potentials. Nerve conduction velocity study suggested axonopathy and demyelinating early polyneuropathy. In the Motor Conduction Study there was wide and low amplitude CMAP present in bilateral Median, Ulnar, Common Peroneal and Tibial nerves with normal conduction velocities and normal F wave latency. The Sensory conduction study done on the bilateral median, ulnar and sural nerves revealed normal conduction velocity and normal amplitude SNAP. Thus, the patient was diagnosed with Amyotrophic Lateral Sclerosis and was started on the tablet riluzole 50 mg twice a day and vitamin E supplementation.
CASE 4:
A 37 year old ragpicker by occupation come to the OPD with chief complaints of bowel and bladder incontinence ,erectile dysfunction and weakness and numbness of lower limbs for past 6 years ,gradually progressive and increased in intensity during the past 6months affecting his routine activities .History of snake bite 10 years back patient developed swelling of thigh and difficulty in walking and was asymptomatic for past 5 years from then and his visit to the local clinics were in vain examination revealed-higher mental functions intact with MMSE 27/30 with intact higher mental functions ,motor examination showed hypertonia of lower limbs with exaggerated reflexes of biceps, triceps ,knee ,ankle with plantar extensors bilaterally sensory intact in the upper limb decreased in lower limb history of dysarthria in family gave us differentials of any autosomal dominant neurogenerative disorders or central lesion above pons. MRI spine showed Expansion of dorsal spinal cord with long segment intramedullary lesion with surrounding edema and syrinx.
?EPENDYMOMA ?ASTROCYTOMA
Follow up was done through PaJR group and neurosurgeon opinion was taken and surgical management was suggested.
CASE 5:
A 20-year-old farmer came to our hospital with painful swelling in right ankle, pain is insidious in onset, dull boring type, continuous, aggravating on both active and passive movement impairing his gait and partially relieved by medication. On local examination, no warmth, no redness, tenderness present, decreased mobility of ankle joint. On further investigations, MRI revealed marrow oedema, cortical irregularity, infective changes in talus, calcaneum and navicular bones and tenosynovitis. Post-MRI patient had exploratory ankle arthrotomy. Histopathology showed a 2 x 1 cm tubercular lesion. Follow up MRI showed talonavicular joint destruction with patchy confluent marrow density and he provisionally diagnosed as tubercular arthritis. Full course ATT given but the pain persisted. Xray showed hyperdense lesion. Symptomatic treatment given and its subsided. Repeat Xray findings normal, followed him on a PaJr. After 1 month, he complains numbness on right and ankle joint. On further questioning only sensory loss, no motor loss is observed and suspected incisional injury to the sural nerve, tubercular osteomyelitis-related sural neuralgia, or a mix of both. The patient was counselled and informed of possible nerve damage and offered sural nerve testing, after which steroidal injections and physiotherapy would be the mainstay of treatment, but due to the patient's limited understanding and poor socioeconomic status, no further testing was done. He is under monitoring for nerve function decline.
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CASE 6:
A 28-year-old female, farmer by occupation, presented with chief complaints of pain and weakness in the lower back region, right upper limb and right lower limb for 8 years. Pain is insidious onset, gradually progressive, dragging type aggravates on movements [involving sitting and getting up] and relieved on medication. Patient also reports joint pains which are migratory in nature with morning stiffness. There was no history of swelling, skin changes, rash, difficulty in breathing, fasciculations of the muscles, involuntary movements, changing of speech, spilling of food from the mouth, sweating disturbances or palpitations, fever or vomiting. CNS examination revealed normal cranial nerve function, sensory examination is normal motor examination revealed hypotonia and mild atrophy of the biceps brachii and brachialis internal rotation and adduction affected. The reflex on the right biceps and right supinator were absent. Right knee jerk was graded 1+. right plantar mute. Proximal weakness was also observed. On joint examination, the squeeze test was positive on the 2nd, 3rd and 4th proximal interphalangeal joints on the right hand as well as on the 3rd and 4th proximal interphalangeal joints, 2nd and 3rd distal interphalangeal joints. On Investigations the MRI scan of the brain revealed a few T2 / FLAIR hyperintense lesions on the right side which are oriented perpendicular to the ventricles. The laboratory investigations revealed that the ESR was elevated (25mm/hr), CRP was negative and CK was within normal ranges (147 IU/L). The NCS investigation was done with the exception of the musculocutaneous nerve and sciatic nerve. The report for both the motor as well as the sensory nerve conduction was normal. Needle EMG, Serum protein electrophoresis and re-investigation of the NCS couldn’t be performed due to technical limitations of the PaJR group as well as financial limitations of the patient. Thus, the patient was given a provisional diagnosis of Multifocal Motor Neuropathy and treatment regimen was started with tablet Prednisolone 10mg and Naproxene 250mg.
CASE 7:
A 49-year-old male, businessman by occupation, with history of hypertension, presented with involuntary movements of the head. The patient was apparently asymptomatic till the year 2000. While watching television, he felt the back of the neck and head become stiff, soon after, he experienced involuntary movements of his head, moving from side to side. They were insidious in onset and progressive in nature. It lasted for 5 to 10 seconds and happened 1-2 times a day, few times a week. The involuntary movements of the head were associated with a pin pricking sensation along his spine. By the year 2005, the involuntary movements of the head increased in frequency, duration and severity. At this point, the patient visited a local physician, but the medications did not provide relief. In 2006, the patient visited a higher center, where the doctor prescribed Amitriptyline 0.25 mg and Clonazepam 0.5 mg once daily. These medications provided some relief for 3 months. After which the involuntary movements continued even after increasing the doses of medicines. The patient also tried homeopathic medication, but it did not provide any relief. In 2008, the patient started experiencing reduced sleep, whenever he tried to rest, in supine position, the involuntary movements of the head reappeared, thus he had to lie down on his sides. The patient also started experienced slurring of speech. By the year 2012, the patient developed ataxia which was insidious in onset and progressive in nature. In a year, the patient was unable to walk without support. Past pointing test was positive. He visited a doctor where an MRI was done and the patient was diagnosed with Autosomal Dominant Spinocerebellar degeneration. The patient was treated with Baclofen 5mg and clonazepam 0.5 mg. The patient experienced some relief of symptoms for a few months. He also started ayurvedic treatment, that was found beneficial, for slurred speech -which included chewing the roots of the plant piper longum. The patient stopped taking medication as it was not providing any relief. In 2018 the patient was diagnosed with hypertension and was started on telmisartan 40 mg Once Daily. The patient also complained of constipation and consumes laxatives occasionally. The patient was started on Amitriptyline Hydrochloride 25 mg OD for symptomatic management. There is no history of muscle weakness, abnormal eye movements, dysarthria, loss of sensations, visual or hearing impairment. There are no features of parkinsonism, epileptic seizures, myoclonus. His mother and elder brother was diagnosed and died by autosomal dominant Spinocerebellar degeneration and elder sister and younger sister was diagnosed and died by autosomal dominant spinocerebellar ataxia current treatment includes Amitriptyline Hydrochloride 25 mg OD, telmisartan 40 mg OD and physiotherapy.
CASE DISCUSSIONS:
CASE 1:
Schwann cell differentiation is governed by the expression of certain transcription factors. After receiving signals from axons, immature Schwann cells including NRG1 will increase the expression of some transcription factors such as NFκB, Oct-6, and Brn2. These factors will stimulate initiation of the promyelination stage whereby the Schwann cell will interact with the axon and begin to express the initial myelination marker. An increase in the Krox-20 gene requires Schwann cells to initiate the myelination process and express the specific protein of myelin. In mature nerves, Schwann cells that do not express Krox-20 will remain nonmyelinated cells. In the injury condition, c-Jun and Sox-2 will increase rapidly. This will lead to a decrease in Krox-20 and Schwann cell differentiation. Cross-resistance Krox-20 and c-Jun will stimulate the switch of complex transcription. Promyelination signals from axons such as neuregulin will result in Krox-20 expression via the phosphatidylinositol-3 kinase (PI3K) pathway. The activation of the Janus kinase (JNK) pathway during the injury period will stimulate c-Jun expression. However, the signals that activate these pathways in Schwann cells are still not known.
Demyelination is caused by the entry of M. leprae into Schwann cells as the main target. The entry of these bacteria can cause the demyelination of Schwann cells suspected through the activation of the c-Jun pathway. When damage occurs in Schwann cells, automatically as a form of defense, Schwann cells will repair the damage that occurs, namely, by remyelination. The process of remyelination is influenced by NRG1 and NGF as a neurotrophic factor, as well as the availability of PMP22 and P0 as specific basic materials of myelin in peripheral nerves.
https://www.intechopen.com/chapters/64038
Although M. leprae has been recognized as the causative agent of leprosy for more than a century, little is still known about the pathophysiology of the underlying nerve damage. It probably involves a complicated interplay of both host-inflammatory and bacterial-mediated events
Exploitation of the armadillo model requires careful description of the disease they manifest and the development of armadillo-specific reagents for modern molecular-based studies. The recently derived whole genome sequence (http://www.ncbi.nlm.nih.gov/genome/235) has provided an essential resource in this regard. The expression profile of genes associated with neuronal structure and function during peripheral nerve injury can now be discerned using M. leprae-infected armadillo nerves. Knowledge gained about the pathogenesis and prevention of nerve injury in leprosy might also be translatable to the study of other neurodegenerative diseases.
These advances will facilitate the use of armadillos in piloting new therapies and diagnostic regimens, and will provide new insights into the oldest known infectious neurodegenerative disorder.
https://pubmed.ncbi.nlm.nih.gov/23223615/
An intraneural ganglion cyst is a non-neoplastic gelatinous cyst, which can be found within the epineurium of a peripheral nerve (1). Intraneural ganglion cysts typically lead to signs and symptoms of peripheral neuropathy because of displacing and compression of the nerve fascicles (2).
During the past few years, substantial evidence has been presented to support the articular (synovial) theory for the pathogenesis and findings observed on magnetic resonance imaging (MRI)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779469/#:~:text=INTRODUCTION-,An%20intraneural%20ganglion%20cyst%20is%20a%20non%2Dneoplastic%20gelatinous%20cyst,the%20nerve%20fascicles%20(2)
CASE 2:
The patient's history and examination results suggest a genetic condition that affects the cerebellum and basal ganglia, leading to progressive symptoms such as uncontrolled movements, difficulty swallowing, slurred speech, and urinary incontinence.
The patient’s high-amplitude, low-frequency tremors suggest an essential tremor, which is common in the older adults (1). However, the relatively young age and family history of the patient pull us to a differential of a hereditary neurodegenerative disorder like Huntington’s Disease or Spinocerebellar Ataxia.
The presence of mild ataxia support the diagnosis of a cerebellar disorder (2). The weakness in raising the palate when the patient said ‘AAA’ indicates the involvement of bulbar muscles, which can also be seen in many neurodegenerative disorders affecting the basal ganglia.
The patient's presentation and autosomal-dominant pattern prompted us to consider other differentials that follow a similar pattern, such as Huntington’s disease-like 1, Huntington’s disease-like 2, spinocerebellar ataxia (SCA) type 2, SCA type 17 (3). Of these, HDL2 is the most commonly identified differential, characterized by the presence of acanthocytes (3). SCA can be easily differentiated from HD by MRI findings that show pons and medullary atrophy, in contrast to the caudate and putamen atrophy seen in HD (4).
Based on the patient’s family history and clinical examination findings, a diagnosis of spinocerebellar ataxia (SCA) was considered. SCA is an autosomal-dominant, progressive, neurodegenerative disorder that mainly affects the cerebellum. It can involve other areas such as basal ganglia, and peripheral nerves, which accounts for the patient’s symptoms of bladder incontinence (5).
A genetic analysis was done after taking the patient’s consent. The patient’s EDTA blood sample was tested for SCA1, SCA17, and HD. The results came back positive for Huntington’s Disease, which showed that CAG repeats on one of the alleles at the HD locus fell beyond the normal range.
Huntington’s disease (HD) is another progressive neurodegenerative disorder with an autosomal dominant pattern of inheritance. It arises due to a CAG trinucleotide expansion mutation in the huntingtin protein. The expansion of the polyglutamine (poly Q) tract at the N-terminus of the huntingtin gene occurs when the CAG repeat in HTT is translated. This expanded PolyQ in HTT leads to the emergence of detrimental characteristics, including cytotoxicity and biochemical dysfunction, contributing to neuropathological alterations in the caudate and putamen regions associated with Huntington's disease (HD). Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities | Acta Pharmacologica Sinica (nature.com)
Huntington's disease (HD) primarily manifests as the loss of neurons in the striatum and cortex, but it also impacts various other regions, including the globus pallidus (GP), thalamus, hypothalamus, subthalamic nucleus, substantia nigra (SN), and cerebellum. Among these, the medium-sized spiny neurons (MSNs) of the indirect pathway in the striatum are particularly susceptible, while the MSNs of the direct pathway are relatively preserved in the initial stages. As the disease progresses, the symptoms arise from the degeneration of pyramidal neurons in layers III, V, and VI of the cortex. The early symptoms, on the other hand, can be attributed to cellular and synaptic dysfunction in the cortex. Pathophysiology of Huntington’s Disease: Time-Dependent Alterations in Synaptic and Receptor Function - PMC (nih.gov)
The disorder manifests with a spectrum of symptoms, including chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties (6).
Although chorea is the most common feature in HD, its absence is not unusual, and most patients present with a variable combination of chorea, dystonia, tics, and akinetic-rigid syndrome (7). In the present case, we report the autosomal-dominant hereditary nature of the disease, along with high-amplitude and low-frequency chorea in the hands, and few cerebellar signs.
The treatment for HD is mostly symptomatic - the goal is to reduce the symptoms, provide relief, and improve quality of life. Some of the common drugs used are tetrabenazine (VMAT2 inhibitor), Olanzapine (Atypical antipsychotic), Amantadine (Glutamate antagonist), Rivastigmine (Acetylcholinesterase inhibitor), Fluoxetine (SSRI), Baclofen (GABA antagonist), and Nabilone (Cannabinoid). In this patient, tetrabenazine and Deutetrabenazine (VMAT2 inhibitor) can be used to manage his motor symptoms.
One of the most recent lines of treatment for HD is stem cell therapy. Mesenchymal stem cells, mainly adipose and bone marrow derived, are known to release neurotrophic factors like specific ILs and cytokines to create a neuroprotective environment. Other stem cells that can be used are fetal neural stem cells, neural cell types differentiated from induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs). Pathogenesis and potential therapeutic application of stem cells transplantation in Huntington’s disease - ScienceDirect
CASE 3:
Amyotrophic Lateral Sclerosis, which is also known as “Lou Gehrig’s disease” [1]. It is a fatal neurodegenerative disorder of upper and lower motor neurons characterised by focal onset muscle weakness and rapid disease progression.[2]
Even though, ALS is a comparatively rare disease, the mortality rates are high. Approximately 50% of people diagnosed with ALS live at least three or more years after diagnosis. About 25% live five years or more and up to 10% live more than 10 years [5]. Hence it is the need of the hour to develop, better therapeutics and rehabilitation treatments.
According to modelling studies, ALS involves interactions between molecular and genetic factors, which lead to a reduced uptake of glutamate (due to dysfunction of excitatory amino acid transporter 2).
Mutations in the superoxide dismuates-1 (SOD-1) gene causing accumulation of intracellular aggregates and defective axonal transport. [2]
There also is activation of microglia, which results in secretion of proinflammatory cytokines and subsequent neurotoxicity.
https://onlinelibrary.wiley.com/doi/abs/10.1016/j.pmrj.2013.03.020
Initially, the patient's symptoms were thought to be due to long term neurodegenerative effects of snake bite (snake bite induced myelopathy). Snake venoms are complex mixtures of enzymes, lipids, nucleotides, and carbohydrates. There are three main toxins in snake venom, including hemotoxins, neurotoxins, and cytotoxins which lead to systematic damage, including cerebral complications (1). Among the complications, cerebral hemorrhage, ischemic stroke, cerebral infarction, and secondary inflammation frequently occur after viper envenomings due to hemotoxic enzymes such as snake-venom metalloproteinases (SVMPs), coagulant enzymes, and proteolytic enzyme toxicity (2).
Initially, the patient's symptoms were thought to be due to long term neurodegenerative effects of snake bite (snake bite induced myelopathy). Snake venoms are complex mixtures of enzymes, lipids, nucleotides, and carbohydrates. There are three main toxins in snake venom, including hemotoxins, neurotoxins, and cytotoxins which lead to systematic damage, including cerebral complications (1). Among the complications, cerebral hemorrhage, ischemic stroke, cerebral infarction, and secondary inflammation frequently occur after viper envenomings due to hemotoxic enzymes such as snake-venom metalloproteinases (SVMPs), coagulant enzymes, and proteolytic enzyme toxicity (2).
Cord expansion is a key finding to identify intramedullary tumors; when the cord is normal in size non-neoplastic processes such as a demyelinating disease should also be considered [24]. Relative to the spinal cord, ependymomas are typically hypointense on T1, hyperintense on T2, and enhance with contrast (Fig. 2). They often include areas of cystic change, hemorrhage, necrosis, and/or calcification that may produce a heterogenous signal [24, 25]. Approximately 60 % of ependymomas are associated with an intramedullary cyst rostral or caudal to the tumor
Myxopapillary ependymomas tend to occur in the area of the conus medullaris. Characteristic appearance on imaging is a heterogeneous lesion with isointense cellular components and hyperintense areas of mucin production or hemorrhage (on T1 and T2) [24, 26]. These well-delineated tumors enhance uniformly with contrast.
Anaplastic ependymomas are typically T1 isointense, T2 iso- or hyperintense, and have variable contrast enhancement. Infiltration into surrounding tissue may be visible, making them difficult to differentiate from an infiltrative glioma. Due to their high-grade nature, it is important to screen for CNS metastases with MRI of the entire neuraxis and potentially CSF cytology after surgery.
Though there are some radiographic differences between ependymoma subtypes, imaging alone cannot reliably distinguish histologic grade or exclude other diagnoses [24]. Imaging is therefore most useful for preoperative planning before tissue diagnosis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705940/
On MRI, astrocytomas are typically isointense or hypointense on T1 weighted imaging (T1WI) and hyperintense on T2 weighted imaging (T2WI) (Figures (Figures11, 2). A vast majority of astrocytomas show some level of enhancement on postcontrast imaging. Cysts are a common finding of spinal astrocytomas. These cysts are usually intratumoral and have peripheral contrast enhancement [15]. About 57% of astrocytomas are eccentric in the cord, due to their origination from the cord parenchyma, therefore, may create a focal expansion of the spinal cord diameter or cause displacement of normal spinal parenchyma [12]
A retrospective review of 19 spinal cord astrocytomas found enhancement in 68% of tumors; typically in a focal nodular, patchy, and inhomogeneous pattern with none exhibiting diffuse homogeneous enhancement. This pattern of enhancement aids in distinguishing astrocytomas from ependymomas of the spinal cord, and gives a clue to a more infiltrative process [16]. However, a multicenter retrospective study found that one-third of astrocytomas in its cohort did not show any enhancement on post-contrast MRI, suggesting that lack of enhancement does not always correlate with the level of invasion [16].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759039/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519136/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3009676/
CASE 5:
A neuron is divided into two segments as distal and proximal to the site of injury and both are significantly different from each other 48. The distal part suffers the Wallerian degeneration (WD) while the proximal part goes through the retrograde degenerative changes as well as instigates the process of regeneration. The process of WD initiates within 24-48 hours following injury and emerges at the distal end of the abrasion in case of severe nerve injury
The ends of the discontinued axons stamp themselves and become swollen within a few hours of injury. The site of individual axon becomes degenerated which is proximal to the subsequent node of Ranvier. Moreover, the disintegration of neurofilaments and cytoskeleton also takes place 29-31.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930373/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930373/
CASE 6:
The main clinical feature of MMN is slow progressive or cascading, asymmetric, predominantly distal extremity weakness without objective loss of sensation in the distribution of two or more peripheral nerves without signs of upper motor neuron lesion MMN mainly affects younger people. Upper extremities are usually affected more often and more seriously than the lower ones (4). Proximal weakness is manifested in only 5%-10% of MMN casesThe main characteristic of MMN is the lack of sensory symptoms. Only a few patients complain of discrete paresthesia or a feeling of numbness in the limbs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536289/
CORRELATION WITH THE PATIENT:
ACCORDING TO CRITERIA FOR DEFINITIVE MMN-
1.Asymmetrical weakness without sensory loss at 2 nerves
2.Definitive conduction block not seen
3.Normal sensory conduction velocity
4. Normal sensory conduction 3 nerves tested with no features of UMN Lesion
PROBABLE MMN:
Asymmetrical Weakness without objective sensory loss in distribution
2.a- probable conduction block at ?musculocutaneous nerve and ?sciatic nerve
3.&4.Normal sensory conduction
5. Absense of UMN signs
https://www.aanem.org/Practice/Guidelines/Consensus-Criteria-for-the-Diagnosis-of-Multifocal
Twenty patients had CB and 13 had no CB. Median follow-up time was 7 years. There were no differences between the two groups in term of age, sex, time from onset to diagnosis, anti-GM1 antibody titers, or CSF dataProximal weakness was less frequent in patients with MMN without CB at the last examination (7/20 vs 0/13; p = 0.027). Fewer nerves were involved in patients without CB at the last examination (4.5 vs 2; p = 0.04).
https://pubmed.ncbi.nlm.nih.gov/16924010/
There are several possible explanations for their lack of evident conduction block. Demyelinated motor axons, which may have had conduction block in the past, may all have undergone wallerian degeneration. Alternatively, conduction block may have been confined to sites which are difficult or impossible to study using routine techniquesIn addition, it is difficult to demonstrate conduction block at proximal sites. Although conduction block was not found in 2 patients in whom spinal nerve stimulation was performed, conduction block at the nerve root level is not assessed by this technique. Other electrodiagnostic features of demyelination were present in all our cases as noted in other cases of MMN
https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-4598(199802)21:2%3C243::AID-MUS14%3E3.0.CO;2-2
CASE 7:
CASE 8:
Age, number of lesion sites, size of encephalomalacia, and seizure frequency were independent risk factors for the prognosis of patients with REAE (OR > 1, P < 0.05). Surgical treatment was an independent protective factor associated with the prognosis of patients with REAEvariety of causes can lead to liquefaction and necrosis of brain tissue and the formation of encephalomalacia [9]. These causes include trauma, cerebrovascular disease, and intracranial infection [10]. The pathological manifestations of brain soft focus ranged from early neuronal necrosis to neuronal disappearance and then to glial cell proliferation. There are no nerve cells in the brain softening focus, which does not cause epileptic discharge. The real pathological site of epileptic discharge is the peripheral nerve tissue [11]. The traction of fibrous scar tissue in the brain can embed the remaining normal neurons cause abnormal discharge and disrupt the function of intertwined proliferative cells. It affects the electrical activity of normal neurons, resulting in seizures. A study suggested that glial cells can lead to epileptic seizures through mechanisms such as increasing the excitability of normal neurons, neuronal cluster discharge, and failure to inhibit the excitability of neurons
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9273423/
Encephalomalacia also known as cerebromalacia, is the softening of brain tissue. It can be caused either by vascular insufficiency, and thus insufficient blood flow to the brain, or by degeneration. Encephalomalacia can be the formation of necrosis, or dead tissue, in a portion of the brain due to a partial complete blockage of blood flow to the area, which in turn can be caused by a natural condition or by infection or trauma (TBI). The term encephalomalacia is also used at times to refer more generally to degenerative conditions affecting the brain. If the condition affects the white matter of the brain, it is called leukoencephalomalacia. If it affects the gray matter, it is known as polioencephalomalacia.
https://www.passenpowell.com/encephalomalacia-brain-injury-children-adults/
CAA has now been linked with brain atrophy in regions remote from those directly affected by intracerebral hematomas, and with risk for progressive cognitive decline in the absence of new hemorrhagic strokes. Therefore, CAA is associated with features – brain atrophy and progressive cognitive decline – that are typically considered hallmarks of neurodegenerative disease. Although CAA is usually accompanied by some degree of Alzheimer's disease pathology, the profiles of cortical thinning and cognitive impairment do not fully overlap with those seen in Alzheimer's disease, suggesting that there are CAA-specific pathways of neurodegeneration. CAA-related brain ischemia may be an important mechanism that leads to brain injury, cortical disconnection, and cognitive impairment
The terms ‘neurodegeneration’ and ‘neurodegenerative’ are widely used but without a formal definition in the peer-reviewed literature. The terms are frequently used to refer to a group of neurological conditions marked by death of neurons and supporting cells in the neurovascular unit, with accompanying progressive loss of cognitive and motor functions.
Stroke and other forms of monophasic acute brain injury (e.g., because of trauma) are not typically considered to be neurodegenerative disorders. Therefore, CAA is most commonly conceptualized as a cerebrovascular disease associated with risk of lobar ICH, and not as a cause of neurodegeneration. However, accruing evidence suggests that CAA is not so easy to pigeonhole as either a cause of stroke or neurodegeneration, but instead is an important cause of both of these neurological syndromes. To make my case that CAA should be considered a neurodegenerative disease, I focus on associations between CAA and two cardinal features of neurodegenerative diseases: cognitive decline and brain atrophy
Both are a consequence of cleavage of the amyloid precursor protein to form pathogenic Aβ which aggregates into β-amyloid. In the case of AD pathology, the β-amyloid aggregates in the brain parenchyma in the form of neuritic plaques. In the case of CAA, the β-amyloid aggregates in the walls of small arteries and arterioles. Most patients with CAA also have some degree of neuritic plaques, and most patients with AD have some degree of CAA
pattern of cortical thinning in CAA (Fotiadis et al. 2016) overlaps with AD (Dickerson et al. 2009) in some regions (supramarginal gyrus, superior frontal gyrus, and inferior temporal gyrus), but other regions exhibit more thinning in CAA than AD (occipital cortex and medial frontal cortex) or in AD than CAA (precuneus, angular gyrus, and anterior temporal cortex) (Fig. 2). Overall, there are clear differences between the CAA and AD patterns of cortical thinning.These differences in cognitive profile and regional cortical thinning suggest that neurodegeneration in CAA cannot be solely attributed to the effects of concomitant AD pathology.
https://onlinelibrary.wiley.com/doi/10.1111/jnc.14157
SWOT ANALYSIS:
Strength:
-The PaJR group enabled us to discuss the case extensively and to keep the patient under constant surveillance.
-Eliminated the need for the patient to come multiple times for history and investigations and introducing a platform to communicate their concerns and needs to multiple doctors whenever needed.
-A systematic medical record was formed including all the details regarding the patient’s history, investigations, examinations, and discussions at one place making it easily accessible for medical professional treating this patient in the future.
-It provided a common platform for the doctors to share their thoughts and concerns and discuss regarding a particular case, which could be tracked and recorded.
-Willingness to follow up, give elaborate and accurate details, well documented clinical history, adherence to treatment
-The patient’s doubts as well as concerns were effectively and immediately taken care of by the group participants. This enables the patient to avoid feeling more distressed than she would be thereby getting a platform to freely express and feel temporarily relieved
-The discussions taking place in the PaJR group effectively compiled. The symptoms, the resource material related to explaining these symptoms, any reports of any investigations done as well as the case reports in one place, making it easier to analyze the progression of the condition.
-The need of having the patient to travel to the hospital numerous times only for follow ups of the condition has been eliminated, thereby preserving the patient’s time, and energy.
-The patient found a means of communication, to express his difficulties on a day-to-day basis, these were immediately managed.
Weakness:
-Since the PaJR eco-system is demands a digital mobile, , poor patient with not that device won’t be able to update any new findings or his health status on the group after his discharge.
-There is a risk of losing confidentiality as the patients may not always adhere to de-identification protocols while sharing results, reports and videos.
-Hesitancy from the patient in sharing details to multiple doctors.
-Academic discussions between doctors regarding the case in the group can come across as unempathetic and overwhelm the patient.
-Lack of face-to-face consultation further lacking human touch is a major drawback as it would not form an ideal doctor patient relationship.
-The news to the patient would be communicated over the phone, making it difficult to understand the patient’s reaction. There was a loss to follow up in this patient reasons of which include lack of patients motivation and lack of understanding of the motive of the platform.
-Inability of physician to keep a tally due to excessive number of patients
-Since the patient resides far away, there was a language barrier between the patient and the doctor in charge.
Opportunity:
-The PaJR group provided an opportunity to many medical students and doctors to get an insight of the case and present their individual discussion about the case.
-It also provided a platform where the patient and their attender could update his condition .
-More organized ways of handling multiple PaJR groups can be explored.
-This approach allowed an open discussion of the rehabilitative treatment for the patient.
-Due to the adequate resources as well as properly documented symptoms, investigation reports, as well as case reports, the information could be effectively used for research modalities.
-This approach allowed a detailed history and an understanding of how the disease affected the individual in terms of day-to-day activities.
Threat:
-Multiple inputs can cause confusion about the etiology and treatment of the disease.
-Lack of open communication from the patient
-Lack of active participation by the group members.
-Lack of literacy by the patients can render these groups impractical for the patients.
-Inability for members of the group to understand the patient’s problems due to a language barrier.
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