Brain Tumors and Peripheral Neuropathies Flashcards
Genetic syndromes associated with increased risk of developing brain tumors?
Only 5% of primary brain tumors are hereditary and the most relevant genetic syndromes are NF1, NF2, TSC, VHL, mismatch repair deficiency syndromes.
What is Neurofibromatosis Type 1 (NF1), its genetic basis, clinical features, and associated tumor risks?
NF1 is an autosomal dominant disorder caused by an inactivating mutation of the NF1 gene, which encodes neurofibromin. Neurofibromin is a tumor suppressor protein that negatively regulates the RAS proto-oncogene, controlling cell growth and proliferation.
Clinical features include :
- Café-au-lait macules which are hyperpigmented flat spots on the skin.
- Axillary and inguinal freckles.
- Neurofibromas which are benign nerve sheath tumors that can present as either dermal neurofibromas or plexiform. - - - Long bone dysplasia which may include bowing of long bones or pseudarthrosis.
Can lead to optic pathway glioma, brainstem glioma and high grade glioma.
They are associated to neurofibromas, glioma and malignant peripheral nerve sheath tumors.
What is neurofibromatosis 2?
Genetic syndrome with an autosomal dominant inheritance characterized by a mutation of the NF2 tumor suppressor, encoding for the protein merlin.
NF2 causes Bilateral vestibular schwannomas are the most common cancer type (90%), followed by meningiomas (50%) and spinal or intracranial ependymomas (5%).
What is tuberous sclerosis 1 and 2?
Autosomal dominant inheritance. TSC1 is characterized by a mutation in the gene encoding for the hamartin protein and TSC2 for the tuberin protein.
Clinical features include epilepsy, cognitive impairment, autism and behavioral alterations.
What is Von Hippel-Lindau syndrome?
VHL is a syndrome characterized by autosomal dominant inheritance and the typical feature is the presence of hemangioblastomas within the CNS (cerebellum, brainstem, spinal cord) that are prone to bleed and show hyper-enhancement on MRI.
Brain metastasis?
Metastases are secondary brain malignancies and mostly come from the lung (20-50%), breast (5-20%), kidney (7-10%) and melanomas (7-16%).
Metastases arise due to hematogenous spread of cancer cells to the brain, after perforating the basement membrane, going into the blood stream, penetrating the BBB and acquiring brain tropism.
What is the seed and soil theory regarding brain metastasis?
The “seed and soil” theory states that metastasis depends on the interaction between cancer cells (“seeds”) and specific organ microenvironments (“soil”). In brain metastases, tumor cells must adapt to the brain’s unique environment, leading to molecular divergence between the primary tumor and its metastases. This divergence implies that targeted therapies effective against the primary tumor may not work on brain metastases if the relevant mutations differ. Consequently, brain biopsies are often performed to guide appropriate treatment strategies.
Common clinical findings of brain tumors?
Similar in primary and secondary malignancies, depends on the tumor location not on tumor type.
- Focal neurological deficits : hemiparesis (frontal lobe involvement and impairment), aphasia and
memory deficits (temporal), hypoesthesia and paresthesia (parietal), hemianopia (occipital), gait ataxia, vertigo, dysarthria, dysphagia (cerebellum), dysphagia, diplopia, long tract involvement with interference of sensory and motor function (brain stem). - Focal seizures, arising is a specific brain area. They could undergo generalization and could be motor seizures if the involvement is the frontal lobe or others, like paresthesia development, if the involvement is at the level of the parietal lobe.
These findings usually develop over days or weeks.
What is vasogenic edema?
Vasogenic edema, commonly associated with malignant brain tumors, results from the disruption of the BBB, leading to the accumulation of extracellular fluid in the brain parenchyma. On MRI FLAIR sequences, this edema appears as hyperintense areas surrounding the tumor mass, indicating increased water content in the affected regions. The presence of vasogenic edema can exacerbate neurological deficits, increase the risk of seizures and contribute to elevated intracranial pressure.
Treatment option include corticosteroids such as dexamethasone (IV,IM or orally, 2-24 mg per day), osmotic agents such as mannitol and hypertonic saline used in severe cases. Loop diuretic such as furosemide to enhance fluid removal.
A combination of these therapies can be used.
Intracranial hypertension?
Intracranial hypertension refers to elevated pressure within the skull, leading to a range of neurological symptoms.
Common manifestations include : headache, nausea, vomiting, visual disturbances, ocular deviations, altered consciousness.
In advanced stages Cushing’s triad may develop characterized by hypertension, bradycardia and irregular respiration.
Additionally it can cause brain herniation, a life threatening condition where the brain tissue is forced across structures with the skull.
IH can be caused by brain tumors, abscesses, head injuries, infections, vascular disorders and hydrocephalus.
IH can also be idiopathic.
Different types of brain herniation?
Brain herniation occurs when increased intracranial pressure forces brain tissue to shift across structures within the skull.
1. Subfalcine (Cingulate) Herniation : The cingulate gyrus is pushed beneath the falx cerebri, potentially compressing the anterior cerebral artery and leading to ischemia.
2. Uncal (Transtentorial) Herniation : The medial temporal lobe (uncus) shifts downward through the tentorial notch, compressing the brainstem and cranial nerve III, resulting in pupil dilation and impaired eye movement.
3. Central Herniation : The diencephalon and adjacent temporal lobes are forced downward through the tentorial notch, causing bilateral pupil constriction and altered consciousness.
4. Tonsillar Herniation : The cerebellar tonsils move downward through the foramen magnum, compressing the medulla oblongata and potentially leading to respiratory and cardiac dysfunction.
5. Transcalvarial Herniation : Brain tissue protrudes through a defect in the skull, such as a fracture or surgical opening, exposing it externally.
6. Upward (Ascending) Herniation: Increased pressure in the posterior fossa pushes cerebellar structures upward through the tentorial notch, compressing the midbrain.
What is hydrocephalus? Types? Treatment?
Hydrocephalus, characterized by an abnormal accumulation of CSF within the brain’s ventricles, can lead to increased intracranial pressure and requires prompt medical attention. The two primary types are obstructive (non-communicating) and communicating hydrocephalus, each with distinct causes and treatment approaches.
Obstructive : forms when CSF flow is blocked along the narrow pathways connecting the ventricles. Common causes include tumors in regions such as the pineal gland, brain stem, cerebellum and basal ganglia. Treatment options include : a third ventriculostomy which is a procedure that creates an opening between the third ventricle and the basal cistern to allow the CSF to bypass the obstruction or a ventriculoperitoneal shunt which involves a shunt system to diverts CSF from the lateral ventricle to the peritoneal cavity.
Communicating : no specific obstruction, CSF is not properly reabsorbed due to dysfunction at the arachnoid granulations. It is associated to conditions like meningeal carcinomatosis, certain secondary brain tumors and hematological disorders like waldenstroms macroglobulinemia. Treatment includes acetalozamide which decreases CSF production.
Imaging in an emergency setting?
After development of some of the previously described conditions the patients usually goes to to ER.
The first line imaging is CT scan, with or without contrast, to easily identify hypodense regions. After CT, a contrast MRI is done to confirm the neoplastic nature, followed by an amino acid PET (thiamine, dopa, fluoroethyl-tyrosine) to visualize metabolically active and highly proliferative regions.
T2 FLAIR and T1 after Gd injection are always performed. The first can show the tumor infiltration and boundaries and edema, while the second is helpful in case of BBB damage. Remember that the edematous area looks the same even in non-neoplastic conditions, but the central core will be different.
What other type of sequences can be used provide insight into brain tumors?
- Susceptibility-Weighted Imaging (SWI) : SWI is highly sensitive to magnetic field inhomogeneities caused by substances like hemosiderin, making it effective in detecting intratumoral hemorrhage and calcifications. Enhances visualization of microbleeds and vascular structures with tumors.
- Diffusion-Weighted Imaging (DWI) : measures the diffusion of water molecules within tissues, with areas of high cellular density, such as tumors, restricting diffusion and appearing hyperintense. This property assists in identifying tumor cellularity and guiding biopsy locations to ensure representative sampling.
- Perfusion-Weighted Imaging (PWI) : evaluates cerebral blood volume and cerebral blood flow, providing insights into tumor vascularity and angiogenesis. Increased CBV and CBF are indicative of high-grade tumors with elevated blood vessel density.
- Magnetic Resonance Spectroscopy (MRS) : analyzes the concentration of metabolites within brain tissue. Elevated choline levels and increased choline/creatine ratios suggest heightened cellular proliferation, common in tumors, while decreased N-acetyl aspartate (NAA) indicates neuronal loss or damage.
What is done after imaging?
After imaging biopsy or resection should be considered. Biopsy is generally preferred if surgery is not an option, in case of older patients, otherwise resection is the gold standard.
What is the WHO classification of tumors of the CNS?
The new classification takes into consideration both the histology and the molecular markers, sometimes essential to establish diagnosis.
- Stains like HE are used to highlight cellular morphology, necrosis, cell density and inflammatory infiltrates.
- Immunohistochemistry uses antibodies targeting specific proteins to determine the cellular lineage and expression of mutant proteins. GFAP identifies astrocytic cells, olig2 marks oligodendrocytic cells, CD34 labels endothelial cells.
- Proliferation index serves as an indirect measure of tumor aggressiveness.
What is the karnofsky performance status score?
The KPS score depicts patients autonomy in daily life to understand the possibility of certain treatments and clinical trials. 70 is the threshold, under it the patient needs assistance in his/her daily life and may not be a candidate for certain treatments.
Treatment for brain tumors? Different types? Complications?
- Chemotherapy —> with alkylating agents leading to cell apoptosis.
- Radiotherapy —> inducing double strand breaks and apoptosis.
Radiotherapy modalities include : conventional radiotherapy that uses x rays to target tumor cells and ion bean radiotherapy which used heavier particles and deliver a big punch without reduced toxicity to surrounding structures.
Radiotherapy techniques include : conformal radiotherapy which shapes the radiation beam to match the tumors geometry, whole brain radiotherapy which irradiates the entire brain (used for multiple metastasis), radio surgery which delivers high dose radiation precisely to the tumor (used for small well defined tumors), and craniospinal radiotherapy which targets both the brain and the spinal cord (used for tumors such as medulloblastoma).
Complications : early complications include acute encephalopathy which can cause headache, vomiting, drowsiness, and exacerbation of pre existing focal deficits.
Late complications include radiation necrosis, stroke and radiation induced leukoencephalopathy.
What is radiation necrosis?
Radiation necrosis involves the death of normal brain tissue post-radiotherapy, often due to thrombosis and obstruction of small arteries. It’s more frequently associated with radiosurgery. Distinguishing it from tumor progression, especially in glioblastoma and necrotic brain metastases, is challenging.
Diagnosis is done with perfusion MRI to assess blood flow as radiation necrosis typically shows reduced perfusion. Magnetic resonance spectroscopy can also be used as it detects metabolic changes, elevated lactate suggests necrosis.
Treatments include corticosteroids to reduce inflammation and edema, bevacizumab which targets vascular endothelial growth factor promoting BBB repair.
What is radiation induced leukoencephalopathy?
This condition involves extensive damage to the brain’s white matter following radiotherapy, characterized by neural loss, cortical atrophy, and microbleeds. It’s particularly associated with whole-brain radiotherapy.
Clinical manifestations include cognitive decline, dementia, movement disorders.
Treatment options are limited as corticosteroids and ventriculoperitoneal shunting have shown incomplete improvement.
Chemotherapy regimens? Side effects? CTCAE classification?
- For high grade gliomas, temozolomide is used as first line therapy, while lomustine or fotemustine as second line.
- For low grade gliomas the PVC protocol or temolozomide is used.
- For medulloblastoma there is the use of intra venous platinoids.
- For CNS lymphomas : high doses intravenous methotrexate.
They all share common side effects such as bone marrow toxicity, liver toxicity, peripheral neuropathy and kidney failure.
Common Terminology Criteria for Adverse Effects can be used to record the severity of the side effects. The scale goes from 1 to 5, 5 being death related to AE.
How is the treatment response assessed?
- Bidimensional Analysis : This method involves measuring the two major axes of the lesion on MRI slices. It provides a straightforward way to estimate tumor size and is especially effective for round lesions. For irregular shaped tumor this approach is insufficient.
- Volumetric analysis : This advanced method involves calculating the entire tumor volume, offering a more precise evaluation of the tumor’s size and response to treatment. Can be used for irregular shapes and heterogenous lesions.
- Tumor composition change : As a result of treatment, the tumor’s composition may change. This includes variations in cell density, necrotic areas, or other tissue alterations that can affect imaging results and interpretations.
Tumor recurrence and heterogeneity?
Recurrent tumors can differ significantly from the original lesion. These differences may include:
- Gene Expression Profiles : The genetic makeup of recurrent tumors can shift due to selective pressures from treatment.
- Heterogeneity : Tumors like glioblastomas are known for their genetic and structural heterogeneity, making evaluation and management challenging.
Primary brain tumors in children?
Primary brain tumors in children are not that frequent, as the incidence for ages between 0 and 14 is 6 cases per 100,000.
The most common tumors are pilocytic astrocytoma, medulloblastoma and malignant glioma. The most common location for these types of tumors are the cerebellum and the brain stem.
Pilocytic astocytoma?
Most common primary brain tumor in children. The most typical location is the cerebellum. It is a benign tumor as it grows slowly over time although due to the location it can cause insidious symptoms such as : difficulty swallowing, slurred speech, diplopia.
This tumor is always a WHO grade I tumor.
The most common pathway alteration is the MAPK signaling pathway. Genes involved are BRAF, FGFR1, FGFR2 and FGFR3.
Prognosis and treatment : it has a favorable prognosis and the 10 year survival rate is close to 100%. Primary treatment is surgery, once the tumor has been resected the patient can be considered cured. The patient must only do regular MRI scans to keep everything under control and in most cases we do not see reoccurrence (<5%).
If total resection is not possible reoccurrence rate is higher (up to 50%). In this case we can observe, radiation over the residue or use oral inhibitors of BRAF or MEK.
Medulloblastoma? Clinical features and subtypes?
Second most common tumor in children. The most frequent location is the cerebellum or the dorsal brain stem. It is an aggressive tumor that grows quite quickly and symptoms develop rapidly. Average age diagnosis is 6.
Clinical features : symptoms develop and consist of headache, nausea, vomiting and gait ataxia. Symptoms are caused either from the tumor mass itself or from obstructive hydrocephalus as the tumor mass often develops very close to the 4th ventricle. One distinct feature is its remarkable propensity for disseminating within the CNS, cancerous cells detach and traverse the CSF.
This tumor metastasis is called drop metastasis as dissemination often occurs due to the influence of gravity, it tend to follow the neuroaxis.
Medulloblastoma only exists as a WHO grade 4 tumor. There are 4 main histological subtypes : classic, desmoplastic/nodular, large cell and anaplastic.
Medulloblastoma main molecular subgroups?
- WNT : subgroup is characterized by mutations in the WNT signaling pathway, specifically involving the WNT/β-catenin pathway. These tumors typically have a favorable prognosis and are associated with children >4 years age old. Predominantly occur in the lower lateral cerebellum
- Sonic hedgehog (SHH): involves mutations in the Sonic Hedgehog signalin pathway. It is further subdivided into SHH-TP53 wildtype and SHH-TP53 mutant subtypes based on the presence or absence of TP53 mutations.
SHH-activated medulloblastomas are associated with a poorer prognosis and can occur in both children <3 years old and adolescent. - Group 3 : subgroup is characterized by high expression of the MYC oncogene and amplifications of the MYC and MYCN genes. Group 3 tumors are typically aggressive and have a poorer prognosis, often occurring in younger children.
- Group 4 : are the most common subtype of medulloblastoma and are characterized by a lack of specific
molecular alterations.
Treatment for medulloblastoma?
Treatment entails craniospinal irradiation with local boost of radiation over the cerebellar mass. This is followed by monthly cycle of IV platinum chemo such as cisplatin or carboplatin.
Very aggressive treatment but necessary to prevent metastasis along the spine.
All patients undergo this treatment scheme, not considering the grade, stage or molecular group. The specific treatment related to the subgroup is more of a reinforcement such as SHH inhibitors.
Diffuse intrinsic pontine glioma? Clinical features? Imaging?
Very aggressive tumor located within the pons diagnosed usually between 6 and 9 years of age.
Clinical features involve a variety of symptoms as patents are quite disabled by this type of tumor. It includes diplopia, facial palsy, motor deficits and cerebellar dysfunction.
Imaging features : extensive infiltration of the pons without contrast enhancement. Deep infiltration of the tumor mass which creates a cavity within the pons.
From a molecular point of view these tumors are defined by the H3 K27M (75%) mutation. These are specific mutations encoding for a histone that is one of the proteins responsible for variation in chromatin conformation, DNA shaping and transcription.
If this mutation is present it is directly considered a grade IV tumor.
Treatment for diffuse intrinsic pontine gliomas? Biopsy?
Due to their location they are generally not resectable.
Biopsy is often omitted due to high risk complications. Even stereotactic biopsy with a trans occipital approach could potentially cause fatal bleeding.
Liquid biopsy can be done to detect mutation. It is a viable way to confirm the diagnosis without the risks of surgery.
Radiotherapy is the standard treatment for DIPG. It is essential to understand that in this case radiotherapy is palliative rather than curative. DIPG are poorly responsive to conventional chemotherapy. Research is going on to look for other alternatives.
Prognosis is poor and the median overall survival around 9-12 month.
Primary brain tumors in adults?
Primary brain tumors are more frequent in adults than in children. Almost 43 cases per 100,000 per year.
The three most common pediatric ones are much less common in adults, the most common in adults are meningiomas, pituitary adenomas and glioblastoma.
The incidence of meningiomas and glioblastomas particularly increases with age until 45-50 years old and then hits a plateau.
Meningiomas? Clinical features? Imaging? Histo-molecular features?
Most common adult primary tumor. Risk developing it increases exponentially with age after 65 years of age.
They exhibit a notable female prevalence of 3.5:1, this is attributed to hormonal influences as meningiomas possess receptors for both estrogen and progesterone on their cell surfaces.
Predisposing factors include history of previous radiotherapy and individuals with NF2.
Clinical features : they are generally considered benign tumors as they develop very slowly. They cause insidious symptoms like headache, focal deficits and seizures. These all develop over several months or years.
Imaging : it is a very well defined lesion with homogenous contrast enhancement and a dural tail (linear image at base of mass which is the connection between the meningioma and the meninges), hyperostosis (abnormal thickening) of adjacent bone and intralesional calcifications. It is challenging to tell wether the tumor is growing inside the brain parenchyma (intra-axial) or outside (extra-axial).
How does menopause affect meningiomas prevalence in females?
Menopause, which entails a decline in estrogen and progesterone levels, may potentially reduce the female prevalence of meningiomas by diminishing hormonal stimulation of tumor growth, but we need to remember that the effect of estrogen/progesterone is cumulative, the tumor will develop after YEARS of stimulation.
Histo-molecular features of meningiomas?
Meningiomas exhibit distinct molecular patterns based on their location due to regional gene expression differences in meningeal cells :
- Convexity Meningiomas (50-70%) : located on the cerebral hemisphere, often associated with NF2 somatic mutations.
- Skull Base Meningiomas (30-40%) : Commonly harbor mutations such as KLF4/TRAF7, often linked to the secretory histological subtype.
- Spinal Cord Meningiomas (10%): Frequently have SMARCE1 mutations, particularly in the clear cell histological subtype.
Genetic and Clinical Distinctions : NF2 mutations are also implicated in neurofibromatosis type 2, but differ in sporadic meningiomas where they are somatic mutations (tumor-specific) rather than germline mutations (present in all cells).
Most meningiomas are benign (WHO grade 1), but 10-20% are aggressive (WHO grade 2-3) with biologically invasive behavior, such as cortical infiltration.
Aggressive Meningiomas and Clinical Presentation : WHO grade 2-3 meningiomas often present with significant peritumoral edema visible on MRI, especially in convexity meningiomas, and have a tendency to infiltrate adjacent brain tissue despite originating outside the parenchyma.
Management and treatment of meningiomas?
If meningioma is suspected on MRI we have two options based on whether the patient has symptoms. If no symptoms then we observe if the patient has symptoms we intervene.
Good clinical condition entitles usually surgery and analysis of histology plus potential medical therapy.
Poor clinical condition entitles SRS or RT.
After analysis of histology plus potential—> WHO grade I leads observation, with WHO grade II or III the patients usually receives SRS or RT.
Conventional chemotherapy isn’t typically used due to its limited effectiveness.
Medical therapy is only considered in cases where surgical and RT options have been excluded. In those cases hydroxyurea is occasionally used.
What are diffuse gliomas?
Diffuse gliomas are a heterogenous group of primary brain tumors that arise from glial cells, which are supportive cells in the central nervous system. These tumors are characterized by their infiltrative growth pattern, meaning they spread diffusely throughout the brain rather than forming distinct, well-defined masses.
Can arise from different types of glial cells, including astrocytes, oligodendrocytes, and ependymal cells, and they are classified based on their histological features and molecular characteristics.
Tumors are graded from 2 to 4 based on aggressiveness. In this class we consider glioblastoma and IDH mutant gliomas.
Glioblastoma? Clinical features? Imaging?
It is the most common malignant primary brain tumor, peak incidence is between 60 and 80 year of age, it has a slight male predominance.
Clinical features —> focal deficits, seizures (quite common), rapidly progressive cognitive and behavioral changes, symptoms of intracranial hypertension such as headache, nausea and vomiting.
Imaging —> infiltrating lesion with peripheral contrast enhancement and necrotic cystic core surrounded by perilesional edema. The first is seen as hypointense area on T1 weighted MRI and the latter is seen as hyper intense areas on FLAIR images.
Typically exhibit contrast enhancement on post-contrast MRI scans due to disruption of the blood-brain barrier and increased vascular permeability within the tumor.
Signs of hemorrhage can be detected on susceptibility weighted imaging (SWI) where you can see hemosiderin deposits.
Classification of glioblastoma?
GB is always considered a WHO grade IV and it is defined as a diffusively infiltrative astrocytic glioma that is IDH wild type and exhibits microvascular proliferation or necrosis or one more of the following : TERT promoter mutation, EGFR amplification or chromosome 7 gain/10 loss
This means that even IDH wild type grade II and III gliomas can be classified as GB if they have one or more of the previous molecular alterations.
Treatment, prognostic factors and therapeutic options at recurrence of glioblastoma?
First line treatment is the STUPP protocol which is concomitant radio-chemotherapy with daily temozolomide for 6 weeks followed by monthly cycles of adjuvant temozolomide (5 days every 4 weeks).
In case of side effects the dose can be reduced. Only in case of very low platelet count can you stop treatment.
Side effects of temozolomide include thrombocytopenia, leuko/lymphopenia, nausea and vomiting, liver toxicity. Side effects of RT include acute encephalopathy and radiation necrosis.
Prognostic factors include age, KPS and MGMT promoter methylation. A patient less than 70 years old with more than 70 on KPS is a favorable situation. The higher the age and lower the KPS the more unfavorable the situation is.
MGMT encodes for a protein that is responsible for repairing DNA. If the gene is methylated the gene is not expressed, therefore the cells are more prone to die from the damage from chemotherapy.
Therapeutic options at recurrence —> typically tumor recurrence occurs 8 months after diagnosis. Second line treatment may include surgery, re irradiation and medical therapy with alkylating agents like lomustine and bevacizumab. Despite all median overall survival does not exceed 15 month.
IDH mutant gliomas? Subtypes? Clinical and imaging features? Histo molecular features?
They are a subtype of diffuse gliomas characterized by mutations in the isocitrate dehydrogenase gene. They can be further classified based on additional genetic alterations :
- IDH-mutant oligodendrogliomas : also carry mutations in the IDH gene, but they are further characterized by co deletion of chromosomal arms 1p and 19q (1p/19q codeletion). This genetic alteration is associated with a better response and a more favorable prognosis. Generally type I or II.
- IDH-mutant astrocytoma : exhibit mutations in the IDH gene and often also show mutations in the ATRX and TP53 genes. Grade II and III and IV astrocytoma are included in this subtype. Mainly effect young adults between 20 and 40 years old with a slightly male prevalence.
Clinical features : mainly included epileptic seizures present in 90% of cases due to the tumor being very infiltrative.
Imaging features : The MRI findings reveal an infiltrating lesion exhibiting hyperintensity on T2/FLAIR sequences and hypointensity on T1 sequences. It’s noteworthy that the glioma appears patchier due to its diffuse nature, lacking a solid mass appearance. Additionally, cortical visibility is compromised due to extensive infiltration, hindering clear margin delineation.
Histo molecular : we must identify the IDH mutation and the 1p/19q codeletion to distinguish between astrocytomas and oligodendrogliomas.
Oligodendrogliomas are either grade II or III.
Astrocytomas can be grade II, III or IV. To be grade IV it must exhibit an additional molecular marker such as CDKN2A/B homozygous deletion or microvascular proliferation or necrosis.
What is the IDH mutation?
IDH1 and IDH2 are two genes that encode for isocitrate dehydrogenase 1 and 2, intracellular enzymes responsible for the metabolism of isocitrate.
Normally, these enzymes convert isocitrate to alpha-ketoglutarate. However, mutations in these genes lead to the conversion of isocitrate to 2-hydroxyglutarate (2HG), an oncometabolite that accumulates in the cell cytosol.
This abnormal accumulation induces widespread DNA chromatin modifications, resulting in global DNA methylation.
The most common mutations in IDH1 and IDH2 are R132H and R172K missense mutations, respectively, occurring in approximately 90% of cases.
MR spectroscopy can be used to identify 2HG in tumors.
Prognosis, treatment and targeted therapy for IDH mutant gliomas?
Prognostic factors include age, extent of resection by surgeon, molecular group and WHO grade, and neurological deficits.
Currently there are several clinical trials exploring the efficacy of small molecules that are inhibitors of the IDH mutant enzymes. Some molecules inhibit both IDH 1 and IDH 2 while others inhibit specifically one or the other.
Primary CNS lymphomas? Clinical and imaging features? Diagnosis, prognosis and treatment?
Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma that originates in the brain, spinal cord, or cerebrospinal fluid (CSF) without involvement of other parts of the body at the time of diagnosis (are B-cell lumphoma). Prevalent in less than 2% of adult brain tumors
Mainly in elderly patients or immunocompromised patients (HIV or HSCT).
Clinical features : patients present with cognitive and behavioral changes, headache, seizures and other neurological deficits.
Imaging features : single or multiple supratentorial lesions with hyper dense appearance on CT often located in corpus callosum or near ventricles.
Diagnosis and staging : they are DLBCL in 90% of cases with MYD88 anf CD79B mutations. Diagnosis should include HIV blood test, lumbar and ophthalmological evaluation to confirm no lymphoma in other parts. MRI evaluation and histopathological analysis.
Prognosis and treatment : treatment ranges from high dose methotrexate IV every 2-3 weeks for 4-6 cycles, ARA-C, thiothepa and rituximab might be added. High dose chemo with ASCT.
Novel approaches include ibrutinib, lenlidomide and CAR-T cells.
Diagnosis and treatment of brain metastasis? Imaging and surgical resection?
Brain metastasis refers to the spread of cancer cells from a primary tumor located outside the brain to the brain. The cancer cells typically travel through the bloodstream or lymphatic system and establish new tumors within the brain tissue. Most common primary tumors : lung, breast, renal, melanoma and colorectal.
Peak age is between 50 to 75. Brain metastasis usually involve brain parenchyma and or the meninges.
Clinical features : findings can be incidental during scheduled surveillance imaging or they can be due to symptoms such as headaches, seizures, cognitive changes, weakness’s visual disturbances etc.
Imaging : Brain metastases often present as multiple lesions scattered throughout the brain rather than a single mass. However, they can also occur as solitary lesions. On contrast-enhanced MRI or CT scans, brain metastases typically appear as ring-enhancing lesions. This enhancement pattern is due to disruption of the blood-brain barrier and contrast agent accumulation around the periphery of the tumor.
Surgical resection should be considered should only be considered in patients with 1-3 brain metastasis especially if the lesions are bigger than 3cm in diameters, have large areas of edema and lesions cause obstructive hydrocephalus.
SRS can be used, it focuses radiation beams to rpecily target abnormal tissue and can be used on multiple lesions simultaneously. The two types used are gamma knife and cyber knife.
What are immune check point inhibitors? Other targeted therapies for brain metastasis?
Immune checkpoint inhibitors are a class of cancer immunotherapy drugs that work by blocking inhibitory pathways in the immune system, allowing it to recognize and attack cancer cells more effectively. Should be used in junction with surgical procedures and SRS since it complements the overall treatment.
Targeted drugs specifically target molecular abnormalities or pathways implicated in the growth and survival of cancer cells within the brain. Common molecular targets in the brain include mutations in genes such as EGFR, ALK, BRAF.
What is meningeal carcinomatosis?
Meningeal carcinomatosis consists of the invasion of leptomeninges by cancer cells.
Clinical presentation —> Manifests with subacute progressive signs and symptoms related to multifocal nervous system dysfunction : headache, nausea, vomiting, mental changes, CN palsies, focal or irradiating neck and back pain.
Imaging : spinal and brain MRI shows either diffuse or focal enhancements often with modularity, there also may be thickening of the meninges. Nodules may be present along the spine, cerebral convexity and the ependyma.
CSF analysis may be helpful because it discloses tumor cells on cytological analysis.
Prognosis and treatment : prognosis is poor, treatment options are available to increase quality of life and potentially extend survival. Treatment options include systemic chemotherapy, targeted therapy, intrathecal chemotherapy and palliative radiation.
What are the components of the peripheral nervous system and their functions?
The peripheral nervous system includes:
1. Cranial nerves : 12 pairs that can be sensory, motor, or mixed.
- Spinal nerves : Originate from the spinal cord and have both motor (anterior horn) and sensory (dorsal root ganglia) components.
- Autonomic system : Includes the sympathetic system (originates from thoracic spinal cord) and the parasympathetic system (originates from brainstem and sacral spinal cord). Motor fibers are always myelinated for fast conduction, while sensory fibers can be myelinated or unmyelinated.
What are the differences between myelinated and unmyelinated fibers, and why are they important?
Myelinated fibers have axons wrapped in a myelin sheath, allowing saltatory conduction, which enables rapid signal transmission.
Unmyelinated fibers have multiple axons surrounded by a single Schwann cell, resulting in slower conduction velocity.
All motor fibers are myelinated for quick muscle response, while sensory fibers can be myelinated or unmyelinated (e.g., slow C fibers). This difference is crucial for ensuring that motor signals are transmitted quickly and sensory signals vary based on the type of stimulus.
What types of structural damage can occur in peripheral nerves, and how do they differ?
Peripheral nerve damage is categorized as :
- Axonal damage: The axon degenerates from the periphery towards the cell body, often termed “dying back.” This can disrupt communication between neurons.
- Demyelinating damage: Myelin is damaged segmentally, often by immune mechanisms. Some areas of myelin remain intact, while others are destroyed, impairing conduction speed. Both types of damage result in neurological deficits but have different pathophysiological mechanisms.
How should you approach a patient suspected of having a PNS disorder?
- Consider peripheral neuropathy as a potential cause of sensory or motor symptoms. Rule out brain or spinal cord dysfunction using a neurological exam.
- Identify the affected nerves by examining the topographical distribution of dysfunction.
- Assess the disease course (acute, subacute, or chronic), as the timeline can suggest different causes.
- Determine the type of damage:
• Motor, sensory, or autonomic involvement.
• Length-dependent or non-length-dependent damage.
• Axonal, demyelinating, or mixed damage.
What are the symptoms and signs of peripheral neuropathy?
- Motor symptoms: Muscle weakness, cramps, spasms, fasciculations, and muscle atrophy. Use the MRC scale to assess muscle strength and symmetry.
- Sensory symptoms: Include hypoesthesia, sensory ataxia, paresthesia, and neuropathic pain.
- Reduced deep tendon reflexes: A key sign of peripheral neuropathy, contrasting with increased reflexes in CNS damage.
- Trophic changes: Muscle atrophy and bone deformities, indicating chronic neuropathy.
- Dysautonomia: Signs like orthostatic hypotension, bladder dysfunction, anhidrosis, or sexual dysfunction due to autonomic fiber damage.
What clues help differentiate peripheral neuropathy from CNS disorders?
- Motor and sensory distribution : Peripheral neuropathy typically involves specific nerve distributions, while CNS damage follows different patterns.
- Deep tendon reflexes : Decreased in peripheral neuropathy; increased in CNS damage (e.g., due to brain tumor or myelitis).
- Autonomic dysfunction : Common in small fiber neuropathies but less so in CNS disorders.
- Trophic changes : Chronic peripheral neuropathies often cause muscle atrophy and deformities, rarely seen in CNS damage.
What are the types of topographical distribution of PNS dysfunction, and what do they indicate?
Peripheral nerves are widely distributed throughout the body, and assessing which nerves are affected is crucial for determining the cause of dysfunction. The topographical distribution of nerve damage can be classified into five categories:
• Mononeuropathies: Only a single nerve is affected, usually due to compressive neuropathies, such as carpal tunnel syndrome.
• Mononeuropathy multiplex: A few non-adjacent nerves are affected, often caused by vasculitides, which produce a patchy pattern of nerve involvement.
• Plexopathies: All the nerves of a plexus innervating a limb are affected, commonly seen in brachial plexus injuries.
• Polyneuropathy: Involves multiple distal nerves, typically bilaterally, and is the most common presentation in clinical practice, often affecting lower or all four limbs.
• Polyradiculoneuropathy: Involves both proximal (roots) and distal nerves, usually linked to dysimmune causes such as polyradiculoneuritis.
How does the course of peripheral neuropathies help identify their causes?
The course of peripheral neuropathies—how quickly symptoms develop—provides clues about their underlying causes:
• Acute peripheral neuropathies: Develop rapidly and are always acquired. Causes include dysimmune conditions (e.g., Guillain-Barré Syndrome), toxic exposures (e.g., heavy metals), dismetabolic disorders (e.g., porphyria), and infections (e.g., Lyme disease, HIV, rabies, West Nile virus).
• Subacute peripheral neuropathies: Progress more gradually and share some causes with acute forms, including dysimmune conditions (e.g., paraneoplastic syndromes, vasculitis), as well as dismetabolic or toxic/iatrogenic factors (e.g., vitamin B12 deficiency, certain drugs).
• Chronic peripheral neuropathies: Progress slowly and may be either acquired or hereditary. Acquired causes include dysimmune conditions (e.g., CIDP) and dismetabolic issues (e.g., diabetes, uremia). Hereditary causes include Charcot-Marie-Tooth (CMT) disease and inborn errors of metabolism.
How do we assess the type of damage in peripheral neuropathies?
To assess the type of damage in peripheral neuropathies, we evaluate:
1. Affected components: Determine if motor, sensory, or autonomic components are involved (or a combination).
2.Type of damage: Identify if the damage is primarily demyelinating (affecting myelin) or axonal (affecting axons). In many cases, the damage is mixed, as axonal damage can occur secondary to demyelination.
- Length dependence: Determine if the damage is length-dependent, with more severe damage in distal portions compared to proximal portions.
This process involves clinical exams for motor and sensory damage and additional studies like electroneurography to measure nerve conduction parameters.
What information does electroneurography provide in diagnosing peripheral neuropathies?
Electroneurography, a key diagnostic tool for peripheral neuropathies, evaluates nerve conduction by measuring:
- Amplitude of action potentials: Indicates axonal integrity; lower amplitudes reflect axonal loss.
- Latency: Reflects myelin integrity; increased latency indicates slower conduction due to demyelination.
- Velocity: Measures the speed of conduction; reduced velocity also suggests demyelination.
Commonly examined nerves include the median, ulnar, and radial nerves in the upper limb, and the peroneal, tibial, and sural nerves in the lower limb. These studies help monitor disease progression by comparing parameters over time.
What information does electroneurography provide in diagnosing peripheral neuropathies?
Electroneurography, a key diagnostic tool for peripheral neuropathies, evaluates nerve conduction by measuring:
- Amplitude of action potentials: Indicates axonal integrity; lower amplitudes reflect axonal loss.
- Latency: Reflects myelin integrity; increased latency indicates slower conduction due to demyelination.
- Velocity: Measures the speed of conduction; reduced velocity also suggests demyelination.
Commonly examined nerves include the median, ulnar, and radial nerves in the upper limb, and the peroneal, tibial, and sural nerves in the lower limb. These studies help monitor disease progression by comparing parameters over time.
What are the diagnostic tools used to determine the etiology of peripheral neuropathies?
Diagnostic tools include:
1. Blood tests: Help identify infectious (e.g., HIV, Lyme) or dysmetabolic conditions (e.g., vitamin deficiencies, diabetes).
2. Cerebrospinal fluid (CSF) analysis: Useful for polyradiculoneuropathies like Guillain-Barré Syndrome (characterized by albuminocytologic dissociation) or neoplastic meningoradiculitis.
3. Imaging (US/MRI): Ultrasound is used for localized nerve entrapments (e.g., carpal tunnel), while MRI evaluates nerve roots or plexuses for inflammation or structural abnormalities.
4. Genetic testing: Performed if a hereditary neuropathy is suspected, based on family history or characteristic deformities (e.g., Charcot-Marie-Tooth disease).
5. Nerve biopsy: Rarely done due to its invasive nature and risk of sensory deficits. It is used when suspecting vasculitis or lymphoma. Typically, the sural nerve is biopsied as it is easily accessible and purely sensory.
6. Skin biopsy: Used to diagnose small fiber neuropathies, which affect distal nerve fibers in the epidermis and dermis. Nerve conduction studies are normal in these cases, so a punch biopsy (2-3 mm) from the foot, calf, or thigh is necessary to confirm reduced fiber density.
What specialized studies can be performed to assess nerve root conduction, and when are they used?
Specialized studies like F wave and H wave are used to assess nerve root conduction, particularly when suspecting polyradiculoneuropathy.
• F wave studies evaluate conduction from peripheral nerves to nerve roots and back.
• H wave studies examine reflex arcs involving sensory and motor fibers.
These tests provide insights into conduction near the roots (e.g., cervical spine), which cannot be assessed with standard nerve conduction studies. They are performed to confirm diagnoses and assess the severity of damage.
What is Guillane Barré syndrome? Clinical presentation and paraclinical findings?
It is an acute polyradiculoneuritis and it is always immune mediated. It affects all nerve roots so a quite large involvement of the nervous system. Estimated incidence is 1 in 100.000 per year. It has the peculiarity of being a post infectious disorders, in some cases C. Jejuni related to a gastroenteritis. Typically there is an infection which resolves in a few days, then after 1 to 2 weeks the patient starts experiencing neurological symptoms.
Clinical presentation : typically presents with ascending paralysis, starting with distal motor weakness in the lower limbs (e.g., feet) that progresses to proximal muscles. Motor symptoms are the most prominent and troubling, with patients reporting difficulty standing, rising from a chair, or walking due to rapidly worsening weakness.
Sensory symptoms such as hypoesthesia, paresthesia, and sensory ataxia may occur but are less bothersome than motor issues. Key findings include reduced tendon reflexes, an important hallmark for distinguishing GBS from myelitis, which later shows increased reflexes. If left untreated it may progress to respiratory muscle involvement, cranial nerve involvement, pharynx and larynx weakness and dysautonoimia leading to cardiac arrhythmias.
Paraclinical findings : electroneurography is done but may be normal within the first week of symptom onset, normal results do not exclude GBS. Lumbar puncture with CSF analysis is also done and detects albumonocytologic dissociation ( increased CSF protein without increased cell count), hallmark of GBS. Spinal MRI shows thickened or contrast enhanced lumbar nerve roots, indicating inflammation.
Pathogenesis of GBS?
We distinguish two types of GBS based on the pathogenesis, on the mechanism causing nerve damage :
- AIDP (Acute Inflammaotry Demyelinating Polyneuropathy) —> classical demyelinating form. Nerve damage related to autoreactive T cells mediated by immune response. Pathological studies show patchy multifocal mononuclear cell infiltrated through to PNS, with macrophages.
- AMAN (Acute Motor Axonal Neuropathy) —> also immune mediated but the main cause of nerve damage is antibody deposits. IgGs and activated complement are deposited on nodal and intermodal axolemma, macrophages invade the periaxonal space.
In AMAN nerve damage is associated to autoantibodies that target gangliosides which are glycolipids located on the nodes of ranvier. The immune system develops antibodies against foreign antigens like C. Jejuni which has similar lipopolysaccharides on its surface. This links bacterial infection to autoimmune neuropathies.
Diagnosis and treatment of GBS? DDX?
To diagnose with almost certainty GBS the patient must have :
- bilateral and flaccid weakness of the limbs.
- decreased or absent deep tendon reflex.
- worsening course of disease with a plateau reached.
- finding consistent with GBS on nerve conduction studies.
- albuminocytologic dissoaciation.
- absence of DDX for weakness.
DDX include CMV, Lyme disease, HIV, myelitis, poliomyelitis, vasculitis, myasthenia gravis.
As GBS is life threatening even if we aren’t sure we can start treatment. The earlier we get a diagnosis, stop symptom worsening and start treatment the better the outcome.
Treatment for GBS consists in immunotherapy as the primary aim is to control the immune mediated inflammation. First line consists in IV immunoglobulin (0.4 g/Kg for 5 days) or plasma exchange (5 sessions). Mortality rate is just below 10%.
Even if patient survives they usually have some residual complaints.
What is Miller Fisher syndrome and how does it differ from GBS?
Miller-Fisher Syndrome (MFS) is an uncommon immune-mediated subtype of GBS, involving nerve roots with a distinct distribution:
Main symptoms include bilateral ophthalmoplegia, sensory ataxia, and areflexia.
Pathogenesis is associated with autoantibodies against GQ1b gangliosides, highly expressed in ocular muscles and sensory nerves, leading to these specific symptoms.
Key differences from GBS:
• MFS primarily affects ocular and sensory nerves, unlike GBS, which involves motor weakness.
• MFS has a more favorable prognosis as it does not involve respiratory or pharyngeal muscles, making it non-life-threatening.
• Paraclinical findings (CSF analysis and nerve conduction studies) are similar to GBS.
MFS is a monophasic disorder, with symptoms resolving over time.
What is Chronic Inflammatory Demyelinating polyneuropathy? Clinical and paraclinical findings? Variants of CIDP?
It is a chronic version of GBS. It is a polyradicular neuropathy and is also immune mediated. It can affect patients of any age. Sometimes there is preceding infection like in GBS but the association is less pronounced. CIDP is a sensory motor polyradiculoneuritis with a number a variants but in general both sensory and motor axis are involved.
Clinical presentation : to say that is CIDP the symptoms must have been present for more than 2 months and during this time there has been a progressive, step wise progressive or relapsing remitting symptom course. Deep tendon reflex is absent or reduced. Clinical severity is variable.
Paraclinical findings : nerve conduction studies will show typical features of demyelination —> reduced conduction velocity and prolonged distance latency. CSF analysis might observe a type of albuminocytologic dissociation. MRI shows thickening of nerve roots, which is typical of nerve root inflammation. Detection of autoantibodies, not directed at gangliosides like GBS, such as anti contactin 1 or anti neurofascin both expressed at the nodes of ranvier. Overall they are quite uncommon. Nerve biopsy will show onion bulbs which are caused by hypertrophy of myelin sheaths around the axons.
The typical form of CIDP is a sensory-motor polyradicular neuritis, but there are subtypes that are only sensory or only motor or have peculiar features on nerve conduction studies. Atypical CIDP includes Distal Acquired Demyelinating Symmetric (DADS), Multifocal Acquired Demyelinating Sensory and Motor Neuropathy (MADSAM or Lewis-Sumner syndrome - LSS), Pure Motor and Pure Sensory variants.
Pathophysiology and treatment of CIDP? Scales used to measure disability?
Pathophysiology : autoantibodies are found only in a minor fraction of patients, this is because CIDP is probably caused by more than one pathogenic mechanism.
Diagnosis : based on EMG, lumbar puncture, detection of specific autoantibodies like anti TNF155, anti Caspr and anti contactin.
Treatments : treatment differs from GBS as first line is high dose corticosteroids which are not effective in GBS. IV immunoglobulins are also an option.
Since it is a chronic disease treatment must be kept for a longer period and patients usually need maintenance therapy for months to years, usually with low dose corticosteroids, immunosuppressants like azathiprine and monoclonal antibodies like rituximab.
Prognosis is favorable but patients are usually left with some sort of disability like it be needing aid to walk.
There are specific scales to monitor symptoms and disability evolution and treatment response over time, to have an objective parameter to follow up the patients.
ONLS (Overall Neuropathy Limitation Scale) grades the disability that the patient has in regards to the use of his arms and of his legs, and it also has a general score for both upper and lower limb involvement. We also use general scales of disability: Modified Rankin Scale and Berthel Index.
What are acquired length dependent polyneuropathies?
They are PNS disorder in which the peripheral part of the nerve is much more affected than the proximal one. This is due to the decreased number of fibers in distal portions therefore damage is more severe.
These kinds of PNS disorders are characterized by sensory and motor symptoms most affecting hands and feet. They most commonly develop in the context of systemic diseases as peripheral nerves are more prone to damage in the course of systemic diseases.
Most common causes include : diabetes, alcohol, uremia, hypothyroidism, vitamin deficiency, chemotherapy, heavy metals, HIV, critical illness neuropathy and paraproteinuria.
What is diabetic polyneuropathy?
Diabetes is the most common cause of neuropathy, responsible for 50% of cases. Diabetes patients who are at higher risk are those who’ve had diabetes for a long time, have had poor glycemic control, presenting comorbidities such as renal failure.
It is a sensory and autonomic type of neuropathy and it presents with sensory disturbances such as tingling, numbness and pain or sensory loss in feet, symptoms of dysautonomia including bladder and sexual dysfunctions.
Pathogenesis is unclear but since diabetes is known to cause dysfunction in systemic circulation, especially in small vessel, in has been hypothesized that it all stems from chronic ischemic of the vasa nervosum.
Diagnosis requires exclusion of alternative causes.
Treatment is improvement of glycemic control and control for neuropathic pain with pregabalin or gabapentin, duloxetine.
Alcohol abuse leading to neuropathy?
It is the second most common cause accounting for about 10% of cases. Patient who are at increased risk are those who’ve abused daily and for a long time.
It is mainly a sensory length depends neuropathy causing sensory loss, numbness, impaired proprioception.
It is an axonal neuropathy without real treatment. Of course withdrawal from alcohol is important and vitamin B supplement.
What is uremic polyneuropathy?
Uremic polyneuropathy is a sensory and motor neuropathy caused by chronic kidney failure, often exacerbated in diabetic patients with renal failure.
It is characterized by distal sensory loss, weakness in the lower limbs, muscle cramps, and restless leg syndrome, with symptoms arising from the accumulation of uremic toxins, thiamine deficiency, and hyperkalemia.
The neuropathy exhibits axonal degeneration and occasional demyelination. While there is no specific treatment, patients often experience neurological improvement with dialysis or kidney transplantation. Symptom management includes medications for restless leg syndrome, pain relief, and physical therapy to address motor deficits.
Vitamin B deficiencies causing polyneuropathies?
Vitamin B1 (thiamine) —> aka dry beriberi caused length dependent polyneuropathy without neuropathic pain and burning feet sensation. Commonly exacerbates neuropathies with alcohol abuse and uremia.
Vitamin B6 (pyridoxine) —> causes length dependent polyneuropathies, less common.
Vitamin B12 (cobalamin) —> causes subacute combined degeneration which leads to extensive demyelination of white matter of the cerebral hemisphere and of the spinal cord. Causes sensory ataxia, weakness and spasticity.
Heavy metals causing polyneuropathies?
Heavy metals can cause peripheral neuropathies especially intoxication by cadmium, lead and mercury.
Chemotherapy induced peripheral neuropathies?
CIPN are a common complication of cancer treatment, affecting approximately one-third of patients receiving chemotherapy. CIPN arises due to the neurotoxic effects of various chemotherapeutic agents, which damage peripheral nerves at different levels, including the dorsal root ganglia, axon, or nerve terminals. Most drugs cause axonal damage, resulting in a range of symptoms that often necessitate a dose reduction or a change in treatment to prevent disability progression.
Common drugs include platinum compounds like cisplatin, taxanes like docetaxel, vinca alkaloids like vinecristine and proteasome inhibitors like bortezomib.
What is critical illness polyneuropathy?
CIP is a type of neuropathy commonly seen in patients with prolonged ICU stays, often associated with systemic complications such as exposure to toxins, sepsis, organ insufficiency, or multi-organ failure. It typically becomes apparent when patients awaken from sedation or are weaned off mechanical ventilation.
CIP manifests as a symmetrical, length-dependent sensory-motor axonal polyneuropathy, characterized by muscle weakness, varying degrees of sensory loss, and reduced deep tendon reflexes. In extreme cases, it may coexist with critical illness myopathy, where muscles themselves begin to deteriorate. While the exact pathophysiological mechanisms remain unclear, contributing factors include oxidative stress, hypoxemia, pro-inflammatory cytokine production, and ion channel dysfunction, all of which disrupt normal homeostasis.
Paraproteinemia as a cause of polyneuropathy?
- In the context of IgM monoclonal gammopathy of undetermined significance and waldenstrom macroglobulinemia monoclonal components may accumulate in blood and then deposit forming aggregates within the nerves triggering inflammation.
- POEMS syndrome —> Polyneuropathy, Organomegaly, Endocrinopathy, Myeloma protein, Skin changes.
- AL amyloidosis —> acquired amyloidosis caused by deposition of amyloid fibrils composed of Ig light chains in many organs such as heart, GI tract, liver, and ultimately within the nerve causing peripheral neuropathy.
What are genetic polyneuropathies?
They are suspected when symptoms follow a chronic evolution over several years. Among elements suggesting the possibility of genetic polyneuropathies we can find hand or feet deformities, muscle atrophy and skin changes.
Genetic polyneuropathies can be axonal or demyelinating, motor, sensory and or autonomic. What is common is that all nerve are generally equally affected.
What is Charcot-Marie Tooth disorder?
Also known as Hereditary Motor and Sensory Neuropathy, it is the most common hereditary neuromuscular disorder. Typical onset is during the first decades of life with very slow progression.
Presents with —> muscular atrophy and sensory loss in the distal portion of lower limbs, bone deformities resulting in pes cavus and hammer toes, scoliosis and deep tendon reflex reduced or absent.
This disorder is also very heterogenous in terms of genetic alterations. More than 40 different genes could be associated with the disorder. Additionally there are different types of inheritance patterns such as autosomal dominant/recessive or X linked.
CMT1 —> is autosomal dominant demyelinating neuropathy and is due to mutation PMP22 in variant A and mutation MPZ in variant B.
CMT2 —> autosomal dominant axonal neuropathy associated to gene MFN2.
CMTX —> X linked gene GJB1/Cx32
Diagnosis is based on assessment of clinical phenotype to understand possibile genetic causes, nerve conduction studies and electromyographies, family history.
What is hereditary neuropathy with liability to pressure palsies?
Also known as tomaculous neuropathy, it is an autosomal dominant disorders caused by PMP22 deletions or intregenic nonsense mutations.
It induces susceptibility to recurrent transient focal compression neuropathies which may be spontaneous or occurring after minor trauma. Patients experience compression palsies at different sites like writs or elbow.
It is called tomaculous bc of the pathological hallmark of the disease, the tomacula, consisting of focal thickening of the myelin seen at nerve biopsy.
Hereditary metabolic disorders causing peripheral neuropathies?
- Fabry disease —> X linked lysosomal storage disorder caused by deficiency of enzyme alpha galactosiderase A which leads to progressive accumulation of globotriaosylcerimde in organs like kidney, CNS, GI tract, heart and also PNS leading to small fiber sensory and autonomic neuropathy.
- Transthyretin amyloidosis —> autosomal dominant disorder caused by missense mutation in TTR gene encoding for transthyretin, a protein produced by the liver, which should be organized in tetramers to function properly. The mutation causes misfolding and aggregation in different organs including the PNS leading to peripheral sensory motor neuropathy, autonomic neuropathy and compression neuropathies.
Compressive mononeuropathies of the upper limbs?
- Carpal tunnel syndrome —> compression of the median nerve at the wrist. The median nerve innervates the first 3 fingers and a portion of the 4th on the palmar side of the hand. The nerve is usually compressed as it has to pass under a ligament which creates a narrow passage. It can occur due to repeated mechanical stress, amyloidosis or pregnancy related to fluid accumulation. Clinical symptoms include numbness, tingling and pain, in later stages muscle weakness and atrophy. Diagnosis is done based on phalen maneuver and tinel sign (percussion over nerve). Treatment include decompressive surgery, physical therapy.
- Radial nerve injury —> compression of the radial nerve which is responsible for innervating a very large number of muscles in the forearm and provides sensory innervation to the dorsal side of the hand. The nerve can be compressed at the axilla due to Saturday night palsy or improper use of crutches, a the spinal groove due to a numerous fracture and posterior to the interosseous nerve. Drop hand is very typical and evocative.
- Ulnar nerve entrapment —> compression of the ulnar nerve at the elbow. The ulnar nerve is responsible for the sensation for the 4th and 5th fingers of the hand both at the palmar and dorsal side and also provides motor innervation to muscles of the hand. In case of compression symptoms like tingling, numbness and paresthesia in the sensory territory of the nerve associated with abnormal flexion of the 4th and 5th finger leading to claw hand.
Compressive mononeuropathies of the lower limbs?
- Meralgia paresthetica —> compression of the lateral femoral cutaneous nerve at the thigh due to it passing below the inguinal ligament. This can happen in cases of obesity or pregnancy due to the increased abdominal volume. Patients experience tingling and unilateral burning pain, and it usually resolves spontaneously over the course of days or weeks.
- Common peroneal nerve entrapment —> compression of the common peroneal nerve while turning around the fibular head as it is a strict contact point between bone and nerve. Being both a sensory and motor nerve its compression may cause sensory loss in anterior and lateral portion of leg, motor impairment resulting in foot drop due to the innervation of the tibialis anterioris being responsible for dorsiflexion of the foot. This type of idiopathic entrapment is seen in patients who experienced a rapid and substantial weight loss or prolonged immobility.
Recap of anatomy of spinal nerve roots?
Nerve roots are where the nerves that connect the brain and spinal cord to the rest of the body begin. They are formed by the merging of:
• Ventral roots : These carry motor signals from the spinal cord to the muscles. They come from cells in the front (anterior horn) of the spinal cord.
• Dorsal roots : These carry sensory signals from the body to the spinal cord. Their cell bodies are located in the dorsal root ganglia (a small cluster of nerve cells outside the spinal cord).
The spinal cord gives rise to 31 pairs of nerve roots, which are grouped as follows:
• 8 cervical (neck region): These control areas like the neck, shoulders, and arms.
• 12 thoracic (upper back): These supply the chest and abdominal muscles.
• 5 lumbar (lower back): These supply the legs.
• 5 sacral (pelvic region): These supply the pelvis and lower body. The anatomy of these can vary slightly between individuals.
The way the nerve roots exit the spine depends on their location:
1. C1 to C7 nerve roots: Exit above their corresponding vertebrae (e.g., C1 nerve root exits above the first cervical vertebra).
2. C8 nerve root and below: Exit below their corresponding vertebrae. This happens because there are 8 cervical nerve roots, but only 7 cervical vertebrae, so the C8 nerve exits below the seventh vertebra, and this pattern continues downward.
Cervical radiculopathy due to disk herniation?
When a single or a few nerve roots are compressed, they can become dysfunctional. The most common cause of nerve compression is disk herniation which occur as a result of continuous stress.
When intravertebral disk herniates it causes compression on the nerve root and the patient will experience sensory and motor symptoms.
Symptoms of compressive radiculopathy include pain, numbness/tingling and weakness in the territory of the affected nerve root and the corresponding deep tendon reflexes may be reduced or absent.
Lumbar radiculopathies?
The lumbar nerve roots more commonly affected are L4, L5 and S1. S1 related lumbar radiculopathy is often called sciatica to define the manifestation related to the compression of this nerve root, caused in the vast majority of cases by disk herniation, resulting in tingling, pain and numbness at the level of the gluteus and posterior portion of the leg to the feet.
What are plexopathies? Types?
With the term plexopathy we refer to a clinical condition in which the entire plexus is damaged. The plexus consists in the union of several nerve roots which gives rise in the end to peripheral nerves; it can considered as the point of junction between the nerve roots originating from the spinal cord and the peripheral nerves. Can be traumatic, compressive, radiation induced or idiopathic.
- Traumatic brachial plexopathy —> brachial plexus is involved and corrisponde to the union of nerve roots from C5 to T1. Trauma is the most common cause.
- Radiotherapy induced brachial plexopathy —> it is typical of women affected by breast cancer receiving RT. Over time patient may experience sensory and motor symptoms due to dysfunction of brachial plexus. The risk is higher in patient : receiving high dose >50 Gy, large RT volume, previous irradiation.
- Neuralgic amyotrophy aka Personage-Turner syndrome —> unusual phenomenon with unclear pathogenesis. Consist in the development of brachial plexopathy leading to intense shoulder and upper arm pain.
