1.Painful neuropathies preferentially involve thinly myelinated A-delta and unmyelinated C-fibers
2.Voltage gated sodium channels generate and conduct action potentials in peripheral nociceptive pathways
3.Nav1.7 is encoded by the gene SCN9A that maps to chromosome 2q24.3
4.Inherited erythromelalgia and paroxysmal extreme pain disorder have been linked to a gain of function mutation of SCN9A
5.Heterozygous gain of function mutations in the SCN9A gene may also cause small fiber neuropathy
2.Often initiated in the first decade of life
3.Painful episodes can be precipitated by exercise, hot weather and viral illness
4.Attacks may be helped by cold
5.The pain is initially restricted to the surface of the affected body part but may also be perceived deeper within the tissue
6.Attacks at times can be aborted by cooling within the first 5 minutes
1.Functional expression studies have demonstrated a variety of changes in channel function that include:
a.The mutant channel being activated at more negative potentials
b.Slower inactivation kinetics in peripheral sensory and sympathetic neurons
c.Reduction of current thresholds in the DRG neurons that causes hyperexcitability and enhanced repetitive firing
d.Depolarizing shift in steady-steady activation that lowers the threshold for single action potentials and supports high frequency firing in DRG neurons.
e.Associated conditions with SCN9A mutations include:
i.Febrile seizures (familial, 3B)
ii.Hereditary sensory and autonomic neuropathy type IID (HSAN2D) (autosomal recessive)
iii.Congenital insensitivity to pain (autosomal recessive)
iv.Paroxysmal extreme pain disorder (autosomal dominant)
v.Small fiber neuropathy (autosomal dominant)
vi.Dravet syndrome (modifier) autosomal dominant
2.Patch clamp studies
1.Paroxysmal Extreme Pain Disorder (PEPD) is caused by heterozygous mutation in the SCN9A gene that is autosomal dominant and maps to chromosome 2q24
1.Bouts of extreme pain usually within proximal regions of the body
2.Excruciating very brief pain of submandibular, ocular and rectal areas
3.Associated flushing of the surrounding skin
4.Autosomal dominant inheritance with incomplete penetrance of various pain components
5.Submandibular and ocular pain is described more consistently than rectal pain
6.Searing pain may be accompanied by bowel movements
7.Four types of painful episodes have been described:
a.Birth crises:
i.Babies are born red and stiff
b.Rectal crisis:
i.Triggered by defecation in infants and young children and emotional upset in older children and adults
c.Ocular crisis:
i.Most often spontaneous severe ocular pain
d.Mandibular crisis:
i.Triggered by eating and yawning
8.Accompanying autonomic manifestations include:
a.Skin flushing
b.Reflex asystolic syncopy
c.Lacrimation
d.Rhinorrhea
e.Between episodes the physical examination is normal
f.Rarely, pain may affect the entire body
1.Functional analysis in vitro of 3 mutant Nav1.7 channels revealed:
a.Reduction in fast inactivation that leads to a persistent sodium current
1.Molecular genetic localization of the SCN9A mutation
1.A small fiber neuropathy is defined as a structural abnormality of small fibers (if painful A-delta 1-4 μ thinly myelinated and unmyelinated C-fibers) are involved
2.Characterized by degeneration of the distal terminations of their nerve endings
3.Gain of function mutations in voltage gated ion channels cause small fiber neuropathy in some instances. The fibers are hyperexcitable but are structurally intact
4.Somatosensory Aδ fibers and C-fibers that innervate the skin:
a.Pass through the dermis to innervate cutaneous structures
b.End as free endings in the epidermis (Aδ fibers become unmyelinated upon crossing the dermal-epidermal junction)
c.Aδ fibers convey episodic well-localized fast pain and cold while C-fibers are slowly conducting and transmit:
i.Innocuous warm sensations
ii.Possibly some innocuous cold
iii.Burning pain
iv.Noxious input from high threshold mechanical, thermal and chemical stimuli
d.Autonomic innervation:
i.Thinly myelinated fibers are a component of preganglionic innervation while C-fibers are a component of postganglionic fibers
ii.C-fibers innervate:
1.Sweat glands
2.Blood vessels
3.The heart
iii.Mutations in nerve growth factor NGF or its high-affinity receptor NTRK1 cause degeneration of nociceptive and sympathetic neurons (HSAN type 5 and type 4 respectively)
e.Small fiber neuropathy (SFN) occurs with mutations in the SCN9A gene that encodes the Nav1.7 sodium channel
2.Pain is most often the presenting symptom; it is usually spontaneous but may be evoked in some patients (mechanical hyperalgesia or allodynia)
3.The pain may be triggered by exercise or increased temperature (also occurs with Fabry’s disease)
4.Motor function, coordination and deep tendon reflexes are normal as are the sensory modalities of light touch, vibration and proprioception
5.There is usually distal loss of pin-prick, thermal sensation and punctate hyperalgesia and dynamic allodynia are occasionally present
1.Molecular genetic testing to delineate the SCN9A mutation
1.Conventional nerve conduction studies are normal and are used to exclude an associated large fiber component of the neuropathy
2.In research laboratories lasers can be used to stimulate A-delta fibers to evoke cortical potentials
3.Microneurography has also been used (research settings) to record small fibers of peripheral nerve fascicles
4.Quantitative sensory testing :
a.Delineates:
i.Detection thresholds
ii.Pain thresholds
iii.Stimulus response functions
b.Is utilized for evaluation of A-beta, A-delta and C-fibers
5.Skin biopsy:
a.A punch biopsy of 3 mm in diameter is a validated techniques for SFN in the usual circumstances (HIV, diabetes mellitus and amyloid)
b.Morphometric analysis utilizing bright field immunohistochemistry or indirect immunofluorescence
c.The biopsy is stained for the ubiquitin hydrolase PGD9.5
d.Intra-epidermal nerve fiber density measurements are made and compared to international standards
e.A decrease in intra-epidermal nerve fiber density with values below the fifth percentile relative to age and gender matched controls makes the diagnosis of SFN in those conditions with structural abnormalities
f.In vivo corneal confocal microscopy is being assessed in the cornea which is innervated by C-fibers
1.Described in a Columbian family
1.Episodes of upper body pain that begin in infancy
2.The pain is triggered by fasting or fatigue, cold temperature, illness and exertion
1.The syndrome is autosomal dominant and is caused by mutations in the gene that encodes TRPA1 on chromosome 8
2.TRPA1 is a non-selective cation channel that is expressed in a sub-population of nociceptors that can be activated by extreme cold or endogenous ligands
3.The mutation is a substitution of a single amino acid in the S4-S5 region of TRPA1 that increases current flow through the activated channel
1.Molecular genetic evaluation to delineate the mutation
2.QST
3.Skin biopsy
1.Described in a kindred with a novel Nav1.7 mutation
1.Erythema and burning pain in the hands since early childhood later spreading to the feet, cheeks and ears
2.Progressive muscle cramps
3.Autonomic features include:
a.Hyperhidrosis
b.Diarrhea or constipation
c.Episodic dry eyes and mouth
d.Hot flashes
e.Erectile dysfunction
4.Small hands and feet (acromesomelia); the brother and father were affected similarly
1.Reduced intra-epidermal nerve fiber density
2.Missense mutation in the SCN9A gene (G856D; C2567G>A) in the proband, his father and brother
3.Functional analysis demonstrated:
a.Hyperpolarization (-9.3 mV) channel activation
b.Depolarizes (+6.2 mV) steady-state fast-inactivation
c.Slows deactivation and enhances persistent current
1.Molecular genetic evaluation to delineate the mutation
2.Skin biopsy
1.Congenital insensitivity to pain and anhidrosis is also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV)
2.The condition is caused by a genetic loss-of-function of the NTRK1 gene on chromosome 1q23.1
3.The NTKR1 gene encodes the neurotrophic tyrosine kinase-1 receptor (TrKA)
4.Nerve growth factor function includes:
a.Surveillance of nociceptive sensory neurons
b.Sympathetic autonomic neuron maintenance
c.A major component of homeostatic mechanisms and when deficient causes defects in development
d.Bidirectional communication between the immune and central nervous system
e.A component of osteoblast / osteo-progenitor differentiation and proliferation (important for fracture repair and consolidation) and normal bone metabolism
1.Insensitivity to pain
2.Anhidrosis
3.Cognitive deficiency
4.Less frequent findings:
a.Impaired temperature sensation
b.Mandibular osteolysis
c.Dental caries
d.Premature tooth loss
e.Repetitive soft tissue and osseous infections (Staph aureus)
f.Self-mutilating behavior
g.Rare microcephaly
h.Urine and fecal incontinence
i.Growth retardation
j.Heterotopic ossification
k.Corneal ulcers
l.Painless fractures
m.Unexplained hyperthermic episodes
n.Repeated traumatic and thermal injuries; tips of the fingers and toes are typically involved
1.There are three major mutations in the SCN9A gene that cause congenital insensitivity to pain:
a.W897X located in the T-loop of domain 2
b.1767X located in the S2 segment of domain 2
c.S459X located in the linker region between domains 1 and 2
2.The mutations result in a truncated non-functional protein
1.Molecular genetic testing to delineate the mutation in SCN9A
2.Short-latency somatosensory evoked potentials:
a.Marked prolongation of central conduction time
3.Microneurography:
a.Delineates abnormal A-delta and C-fiber activity in the skin
4.A negative sympathetic skin response due to lack of sudomotor terminals in the skin
5.Pharmacologic tests of autonomic function are positive
6.Skin biopsy demonstrates:
a.Hyperplastic epidermis with acanthosis and hyperkeratosis
1.Positive regulatory domain containing zinc finger protein 12 (PRDM 12)
a.PRDM 12 proteins are epigenetic regulators that control neural specification and neurogenesis
b.Mutations in the gene cause congenital insensitivity to pain
2.Hereditary sensory neuropathy (HSN I)
3.Hereditary sensory and autonomic neuropathy (HSN II)
4.Familial dysautonomia (Riley-Day syndrome) (HSN III)
5.Congenital indifference to pain (HSN V)
6.Lesch-Nyhan syndrome
7.Nav1.9 mutation (one variant)
1.Nav1.8 is encoded by SCN10A gene that maps to chromosome 3p22.2
1.Predominantly a painful sensory neuropathy
2.Infrequent signs and symptoms include:
a.Dry eyes and dry mouth
b.Orthostatic dizziness
c.Palpitations
d.Diarrhea and constipation
e.Severe progressive gastroparesis (in one patient)
i.A novel heterozygous mutation in the SCN10A gene
f.Brugada syndrome
1.The Nav1.8 mutations:
a.Accelerate recovery from inactivation
b.Enhance response to slow depolarizations
c.Enhance activation at the channel level
d.Produce hyperexcitability of small dorsal root ganglion (DRG) neurons (nociceptors)
2.Molecular genetic analysis to delineate the SCN10A mutation
1.Nav1.7 and Nav1.8 channels are the main generators of the fast action potential in nociceptors
2.Nav1.9 channels modulate the threshold of nociceptor excitability through action on the resting membrane potential
3.Gain-of-function mutations in Nav1.9 may cause:
a.Congenital insensitivity to pain
b.Familial episodic pain
c.Painful neuropathy
1.A family of mixed European ancestry:
a.Onset early in life
b.Rapid pain onset which lasts approximately 20-30 minutes
c.Triggers are gluten and low ambient temperature
d.Pain starts in the joints and then radiates to the arms and legs
e.Rarely pain is associated with neck and facial flushing
f.Pain episodes primarily occur in the afternoon
g.The quality of the pain is primarily burning
h.Clinical manifestations in Japanese families:
i.Infantile recurrent painful episodes; spontaneous relief around adolescence
ii.Autosomal dominant inheritance with mutation in the SCN11A gene that maps to chromosome 3p22
iii.Affected joints in order of frequency are knees, ankles, wrists and elbows
iv.The pain most often recurs on one side of the affected extremity
v.Rarely pain may be localized to the forearms, arm, palms, fingers, thigh and lower leg
vi.The painful episodes last for 15-30 minutes and recur several times per day; it is more frequent at night
vii.Night time crying and sleep disturbance were common in childhood
viii.The painful areas are cold and relief is obtained with warming
ix.The three major subtypes of clinical manifestations with Nav1.9 mutations:
1.L811P mutation is associated with insensitivity to pain
2.G699R, L1158P and 1381T are associated with small fiber neuropathy that occurs in the fifth or sixth decades and are associated with:
a.Burning pain
b.Skin discoloration
c.Autonomic Dysregulation
3.Familial episodic pain:
a.This phenotype has been reported in two Chinese kindreds and a family of mixed European ancestry
1.There are 12 amino acid substitutions of Nav1.9 that are associated with painful disorders
2.7 mutations are associated with gain-of-function
3.Alterations in channel function include:
a.Gating alterations despite no change in resting membrane potential or threshold; this mutation is in the S4 segment
1.Molecular genetic testing to delineate mutations in the SCN11A gene in Japanese kindred
1.Diabetic peripheral neuropathy (DPN) can be generally separated into:
a.Distal symmetric peripheral neuropathy (length dependent)
b.Focal and multifocal neuropathies
i.Multiple mononeuropathy
ii.Lumbosacral, thoracic, and cervical radiculoplexus neuropathies
2.DPN occurs in patients with type 1 (T1DM) and type 2 diabetes mellitus (T2DM)
a.Onset is insidious with a great number of patients remaining asymptomatic for a long period of time
3.DPN involves both large and small fibers in a length-dependent manner
4.Increased vibration and thermal thresholds occur early in the development of DPN
a.DPN symptoms often develop earlier in the course of T1DM
b.Large myelinated fibers may be more severely affected in Type I DPN whereas T2DM involves small nerve fibers
5.Type I and type 2 DM may respond differently to enhanced glucose control; more intense treatment of hyperglycemia in type 1 patients may lead to a lower incidence of neuropathy whereas it appears to have a minimal effect on type II patients
6.Hyperglycemia may be the primary driver of peripheral nerve injury in type I DM
7.Obesity, hypertension, low high density lipoprotein and hypertriglyceridemia may be risk factors for type II patients
8.Generalized risk factors for DPN include:
a.Older age
b.Long duration of diabetes
c.Retinopathy
d.Hypertension
e.Dyslipidemia
f.Hyperglycemic status
g.Insulin treatment
h.History of cerebrovascular disease
i.Foot ulcers
1.Acute painful diabetic neuropathy (APDN) is a distinctive polyneuropathy with two subtypes:
a.Treatment-induced neuropathy (TIN)
b.Diabetic neuropathic cachexia (DNC)
2.Acute painful diabetic neuropathy (APDN) manifestations include:
a.Small-fiber involvement
b.Occurrence after short-term good glycemic control
c.Intense extremity pain
d.Gradual recovery
3.Insulin-induced hypoglycemia may cause acute neuropathic pain
a.Increased mechanical hypersensitivity
b.Putatively the result of decreased glucose levels rather than insulin
4.Acute severe neuropathic pain in the extremities may occur during intensive treatment of patients with type 1 and type 2 diabetes
5.Asymmetric onset motor or sensory deficits (usually symmetrical) are frequently painful but are generally self-limited
6.Length dependent numbness and paresthesia more severe in the feet than the hands is most common. In general, the sensory signs are perceived above the knee before there is involvement in the upper extremities.
7.Less frequently there is lancinating and deep aching pain in the extremities in a length dependent pattern
8.Severe sensory loss is often associated with painless perforating foot ulcers accompanied by autonomic neuropathy
9.Patients with painless neuropathy are often areflexic, have all modality sensory impairment most prominent in the proprioceptive domain
10. A subgroup of patients have severe burning pain, only a slight diminution of proprioception and intact reflexes with concomitant autonomic neuropathy
11. Patients with impaired glucose tolerance may demonstrate burning foot syndrome
1.The development of diabetic painful neuropathy is not understood but is generally considered to be a multifactorial process.
2.Putative mechanisms include:
a.The polyol pathway:
i.Hyperglycemia is associated with increased concentration of intracellular glucose that saturates normal glycolytic pathways
ii.Glucose is shunted into the polyol pathway and is converted into sorbitol and fructose by aldose reductase and sorbitol dehydrogenases
iii.Increased concentrations of sorbitol and fructose cause:
1.Decreased nerve myoinositol
2.Decreased membrane Na+ / K+ - ATPase activity
3.Impaired axonal transport
4.Structural nerve changes
b.Advanced glycation products:
i.The non-enzymatic reaction of glucose with proteins, nucleotides and lipids causes advanced glycation end products (AGEs) that may interfere with neuronal metabolism and axonal transport
c.Oxidative stress:
i.Increased free radical production may occur with hyperglycemia that may damage blood vessels and cause nerve ischemia and facilitate AGE reactions
d.Activation of poly ADP ribosylation that facilitates the caspase 3 system and apoptosis
e.Activate genes that induce:
i.Cyclooxygenase-2 activation
ii.Cause endothelial dysfunction
iii.Decrease Na+/K+ -ATPase pump function
f.Impair C-peptide-related signaling pathways
g.Cause endoplasmic reticulum stress
h.Induces low grade inflammation
i.Neuronal death from hypoglycemia involves excitotoxicity and DNA damage
j.Mechanisms associated with pain in diabetic neuropathy:
i.In diabetic retinopathy, nephropathy and neuropathy there is upregulation of:
1.Vascular endothelial growth factor (VEGF)
2.Insulin growth factor (IGF)
3.Mitogenic cytokines
4.Inflammatory cytokines (TNF-α, IL-6, IL 8)
ii.Upregulation of these trophic factors and cytokines is associated with tight glycemic control and may be responsible for early acute pain
iii.There is experimental evidence for an increase in proinflammatory cytokines with hypoglycemia
1.QST:
a.Vibration thresholds detect mild or subclinical neuropathy
b.Current perception threshold (CPT) to 2000 Hz stimulation correlates best with vibratory thresholds
2.Sudoscan detects electrochemical skin conductance:
a.Proportional to the number of functioning sweat glands
3.Nerve conduction velocity (NCV):
a.Slowed nerve conduction in nerve axons from segmental demyelination
b.Quantifies spread of motor and sensory conduction, amplitude, distal latency and F wave latency
4.Skin biopsy:
a.Assessment of intraepidermal nerve fiber density to detect small nerve fiber neuropathy
5.Corneal confocal microscopy:
a.Assesses the corneal sub-basal plexes of nerve fibers that originate from the ophthalmic division of the Vth nerve:
i.Quantifies corneal nerve fiber length which is reproducible
ii.Sensitive to corneal nerve fiber damage in early stages of DPN
1.Major causes of cobalamin (vitamin B12) deficiency are cobalamin malabsorption due to inability to release cobalamin from food or its binding proteins
2.Food-cobalamin malabsorption syndrome is caused by:
a.Atrophic gastritis
b.Related or unrelated to Helicobacter pylori infection
c.Long-term ingestion of antacids and biguanides
d.Mutations in genes encoding endocytic receptors involved in the ileal absorption and cellular uptake of cobalamin
1.There may be functional B12 deficiency in advanced malignancy:
a.Elevated levels of B12-dependent metabolites, methyl malonic acid (MMA) and / or homocysteine in the face of normal B12 levels – possibly causing neuropathic pain putatively from oxidative stress
b.Vitamin B12 deficiency may affect between 5-20% of older adults. Clinical manifestations in this population are primarily:
i.Cognitive impairment
ii.Dementia
iii.Depression
iv.Motor and sensory neuropathy
v.A combined sensation of numbness and deep aching pain in the legs is common. Active paresthesias occur in both upper and lower extremities
c.Associated neurologic features include:
i.Optic neuropathy
ii.Slight ataxia
iii.Myelopathy
iv.Hyperactive reflexes in the face of atrophy and peripheral neuropathy are suggestive
2.Demyelinating peripheral neuropathy
3.Methyl cobalamin deficiency (the active form of vitamin B12) and is a coenzyme of methionine synthase that is required for DNA and protein methylation
4.Facilitates neurite outgrowth and inhibits neural apoptosis through the extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2) and AkT signaling pathways
2.Serum B12 assays measure the sum of haptocorrin-bound and transcobalimin-bound (holotranscobalamin) B12; only holotranscobalamin is taken up by cells
3.Methionine synthase requires methylcobalamine for remethylation of methionine from homocysteine; homocysteine concentration of >20 μmol/L is suggestive of B12 deficiency in patients with normal folate concentrations
4.In B12 deficiency states increased methylmalonyl-CoA is hydrolyzed to methylmalonic acid. A serum concentration of >280 nmol/L is suggestive of B12 deficiency
5.EMG:
a.A primarily demyelinative neuropathy
6.A low hemoglobin, RBC > 100μ and hypersegmented polymorphonuclear leukocytes; low platelets are characteristic
1.MRI:
a.Methyl malonate increased concentration
i.Decreases total brain volume
b.Homocysteine increased concentration
i.Increased white matter hyperintensities and cerebral infarcts
1.Vitamin B6 in its active form, human pyridoxal kinase (hPL kinase) is a cofactor for over 160 enzymatic reactions that are involved in:
a.Neurotransmitter production
b.Biosynthesis of D-aspartate, L-glutamate
c.Glycine and GABA
d.Serotonin
e.Epinephrine and norepinephrine
f.Histamine and dopamine
2.Pyridoxal (PL) is an inactive form of vitamin B6 and is converted to pyridoxal 5’-phosphate (PLP) by PL Kinase
3.Theophylline and Ginkotoxin (4’-0-methylpyridoxine), an analogue of vitamin B6 decrease PLP as does isoniazide
4.Risk factors for pyridoxine deficiency:
a.Severe malnutrition
b.Sickle cell disease
c.Inflammatory conditions
d.Rheumatoid arthritis
e.Hepatitis and extrahepatic biliary obstruction
f.Celiac disease
g.Renal failure
h.High alkaline phosphatase levels
5.Medical procedures:
a.Hemodialysis
b.Phototherapy for hyperbilirubinemia
6.Medications:
a.Cycloserine
b.Hydralazine
c.D-penicillamine
d.Isoniazid
e.Pyrazinamide
7.Chronic alcoholism
1.Weakness and dizziness
2.Peripheral neuropathy:
a.Early distal extremity numbness
b.Bilateral distal limb burning paresthesias
c.Late mild to moderate distal weakness
d.Sensory ataxia
e.Proprioception and vibration are more affected than pain and temperature
3.CNS manifestations:
a.Depression and irritability
b.Generalized seizures
4.Associated medical conditions:
a.Cardiovascular:
i.Recurrent venous thromboembolism
ii.Possibly increased early myocardial infarction and stroke
iii.Accelerated atherosclerosis
b.Glossitis and cheilosis
c.Seborrheic dermatitis
1.Large doses of pyridoxine cause peripheral neuropathy primarily of myelinated large fibers that arise from the DRG
2.Vacuolization, increased dense bodies, neurofilament aggregates and chromatolysis are noted in DRG neurons and myelinated fibers
3.Argyrophilic axonal neurodegenerative changes affect the dorsal columns
4.Putative mechanisms of increased pyridoxine toxicity include:
a.Impairment of function of other B vitamins
b.Competitive inhibition of pyridoxal phosphate
c.Formation of reactive quinone methide
d.Blockade of local chelation of magnesium
5.Deficiency of pyridoxine interferes with transamination, decarboxylation and synthetic pathways that involve carbohydrates, sphingolipids, sulfur containing amino acids, heme, and neurotransmitters; PLP is a cofactor for glutamic acid decarboxylase and thus its deficiency decreases GABA
2.PLP levels are dependent on albumin levels; low albumin levels can lead to a falsely low level
3.Erythrocyte aspartate aminotransferase (EAST) and the EAST activation coefficient (EAST-AC) are indicators of long term functional pyridoxine status
1.Low levels of thiamine are usually encountered in a setting of malabsorption or inadequate oral intake
2.Risk factors for deficiency include:
a.Alcoholism and associated malnutrition
b.Renal dialysis
c.Prolonged parenteral glucose (TPN)
d.Bariatric surgery
e.Long term diuretic therapy
f.Hyperemesis gravidarum
g.Cachectic cancer patients
3.Thiamine is a water-soluble vitamin absorbed in the jejunum
4.Thiamine combines with adenosine triphosphate (ATP) in the liver, kidneys and leucocytes which forms thiamine diphosphate its biologically active form
5.It is a coenzyme in carbohydrate metabolic pathways that include decarboxylation of pyruvic and alpha ketoacids as well as transketolations in the pentose monophosphate pathway
1.The mildest signs are muscle atrophy in the legs associated with tenderness on compression with loss or depression of ankle and knee reflexes; sensory loss early is in the legs with decreased touch and pain modalities
2.More advanced patients complain of weakness, paresthesias and pain that is insidiously progressive; a subgroup of patients have rapid progression of signs and symptoms that progress over days
3.Initial symptoms are in distal portions of the extremities and progress proximally with the feet more severely affected than the hands
4.In approximately 1/3 of patients the chief complaint is pain and paresthesia
5.Sensory complaints include:
a.A dull constant ache of the feet and legs
b.Sharp and lancinating extremity pain (similar to tabes dorsalis)
c.Cramping and tightness in muscles of the feet and calves
d.Band-like sensations around the legs
e.Cold-like sensations of the feet
f.Heat and burning sensation of the soles to a greater degree than the dorsum of the feet
g.Patient’s symptoms and signs fluctuate and at times are dominated by mechanical dynamic and static allodynia
h.Most patients have greater distal than proximal weakness
i.Severe deep muscle mechanical hyperalgesia is common which is most severe in the legs and feet
j.Reflexes are depressed or absent at the knee and ankle while often preserved in the arms. In patients with severe pain and minimal weakness they may be slightly increased
k.CNS manifestations:
i.Wernicke-Korsakoff syndrome:
1.Wernicke’s syndrome
a.Ophthalmoplegia and nystagmus
b.Ataxia
c.Confusion
2.Korsakoff’s syndrome:
a.Amnestic dementia
b.Confabulation
l.Associated medical conditions:
i.Primarily severe cardiovascular signs and symptoms of heart failure
1.Deficiency leads to decreased transketolase activity that increases pyruvic acid:
a.It is not converted to acetyl-coA and does not enter the Krebs cycle for oxidative metabolism
b.Pyruvic acid is metabolized anaerobically to lactic acid
2.Sural nerve biopsy:
a.Primarily axonal degeneration with some fibers demonstrating segmental demyelination
1.Increased blood pyruvate, alpha-ketoglutarate and lactate
2.Increased serum glycosylate
3.Urinary methyl glyoxal
4.Urinary thiamine and metabolites thiazole and pyrimidine
1.MRI: (Wernicke-Korsakoff):
a.Hemorrhage and enlargement (acutely) of the mammillary bodies, dorsal medial thalamic nucleus and hypothalamus
1.Porphyrins are precursors of heme that are synthesized in a multistep process. Enzymatic defects during the steps of heme synthesis cause distinct clinical syndromes that predominantly affect the skin or the liver and nervous system
2.The acute porphyrias that have periodic attacks of neurovisceral symptoms and neurologic deficits are:
a.Doss porphyria (ALA dehydratase deficiency)
b.Acute intermittent porphyria (AIP)
c.Hereditary coproporphyria
d.Variegate porphyria
1.Are dependent on the enzymatic defect and when it occurs in heme synthesis. Early defects in the synthetic cascades are associated with increased serum concentrations of aminolevulinic acid (ALA) and porphobilinogen (PBG). Enzymatic defects in the later part of heme synthesis cause photosensitivity due to porphyrin accumulation in the skin
1.The liver is the major source of overproduction of heme pathway intermediates in the hepatic porphyrias of which AIP is the most common
2.AIP is caused by a heterozygous mutation in the gene encoding porphobilinogen deaminase (PBGD) that maps to chromosome 11q23.3. It is autosomal dominant
1.The initial and often the most prominent symptom is colicky abdominal pain that is most often generalized and is not associated with rigidity or rebound tenderness
2.Constipation and ileus are frequent concomitants of the pain
3.Attacks may last for days to weeks if not treated and are often associated with vomiting
4.Attacks may be precipitated by dieting, alcohol and estrogen as well as drugs that include:
a.Phenobarbital
b.Dilantin
c.Sulfonamides
d.Griseofulvin
e.Succinimide anticonvulsants
5.The first attacks are rare prior to puberty and attacks are most dangerous during adolescence and early adulthood
6.Most often motor nerves are affected more than sensory but in some patients motor, sensory and autonomic nerves are affected concomitantly
7.Symptoms may begin in the feet and legs and ascend or less commonly there is asymmetric early involvement of the arms and hands and then spread to the trunk and legs
8.There may be proximal weakness of shoulder and pelvic girdle muscles with loss of knee jerks and preservation of ankle reflexes
9.There is rare facial paralysis, dysphagia and ocular muscle weakness
10. Sensory loss that may extend to the trunk is seen in approximately 50% of patients; may have pain in the chest and back
11. Acute neurovisceral pain may be associated with rapidly progressive quadriparesis resembling Guillain-Barré syndrome
12. CNS manifestations include:
a.Confusion and delirium
b.Visual field deficits
c.Seizures
d.Psychosis
13. Associated medical conditions:
a.Tachycardia and hypertension occur in the acute stages (rarely hypotension)
b.Fever and leukocytosis may occur during severe attacks
14. The neuropathy can rarely develop without other symptoms
1.The mutation in PBGD is autosomal dominant with low penetrance. More than 300 PBGD gene mutations have been described all of which cause loss of enzymatic activity from the mutant allele
2.Acute attacks in AIP are precipitated by hormonal and environmental factors that induce hepatic 5-aminolevulinic synthase to produce the porphyrin precursors:
a.ALA dehydratase
b.Porphobilinogen
3.Demyelination of the cerebral cortex and cerebellum is seen in some patients
4.Chromatolysis in neurons of the spinal cord
1.Patients during acute attacks have increases of 5-100 times the urine concentration of ALA and PBG
2.Hyponatremia is frequent; a patient has been studied who demonstrated median eminence of the hypothalamus and hypothalamic-hypophyseal tract lesions: patients may be hypomagnesemic
3.Molecular genetic testing to delineate the mutation in the PBGD gene
4.EMG / NCV
a.The neuropathy may be predominately upper extremity, motor and proximal
b.Predominately a motor axonal neuropathy
1.MRI:
a.Multiple large, contrast-enhancing subcortical white matter lesions
b.Diffusion-weighted MRI is normal
2.MR spectroscopy:
a.Normal
3.The putative mechanism for the lesions is reversible vasogenic edema with transient disruption of the blood brain barrier
4.In many patients the white matter lesions are bioccipital and are partially or completely reversible
1.Also known as plumb porphyria is due to ALA dehydratase deficiency
2.The ALAD gene maps to chromosome 9q32 and encodes delta-amino levulinate dehydratase (porphobilinogen synthase)
3.It is a cytosolic enzyme that catalyzes the second step in the porphyrin and heme biosynthetic pathway
4.Clinical features are seen if there is greater than 90% deficiency of the enzyme
5.It is an autosomal recessive disorder
1.Colicky abdominal pain and vomiting
2.Primarily a motor neuropathy
3.In some patients the acute porphyria occurs during infusion of erythropoietin
2.Lead may unmask occult plumb-porphyria
3.Tyrosinemia type I may occur with the disorder
2.Molecular genetic studies delineate the causative mutation
3.There is no urinary increase in PBG
1.Hereditary coproporphyria (HCP) is caused by heterozygous mutation in the CPOX gene that maps to chromosome 3q11.2
2.Harderoporphyria is a subtype of HCP that is caused by a homozygous or compound heterozygous mutation in the CPOX gene
3.Inheritance is usually AD but AR patients have been reported
1.In general clinical features become manifest when there is ~50% enzyme activity (heterozygous mutation) or homozygous (<10% of activity) mutation
2.The neurovisceral manifestations are similar to those seen in AIP but are less severe
3.Neurologic defects are initiated by drugs, fasting, infections and the menstrual cycle
4.Approximately 50% of patients may be asymptomatic
5.Psychiatric symptoms occur
6.Peripheral neuropathy is primarily motor; sensory symptoms may include pain in the extremities
7.Cutaneous features occur in approximately 30% of patients and include:
a.Vesiculobullous eruptions that involve the face, hands and sun-exposed skin areas
b.Lesions may heal with scarring, increased pigmentation or hypertrichosis
8.Nausea, vomiting, diarrhea are frequent
9.Hypertension may occur during acute attacks
10. Generalized tonic-clonic seizures may occur
1.HCP is caused by mutations in the CPOX gene that:
a.Encodes the enzyme coproporphyrinogen oxidase. This enzyme is the sixth step in the heme biosynthetic pathway that converts coproporphyrinogen III to protoporphyrinogen IX
1.Elevation of urinary ALA and PBG
2.ALA excretion exceeds that of PBG
3.Elevation of fecal coproporphyrin III alone without elevation of protoporphyrin IX distinguishes it from variegate porphyria (VP)
4.Fecal and urinary coproporphyrin III levels are increased 10-200 times normal levels
5.Molecular genetic delineation of the CPOX mutation
1.SPECT:
a.Mild to moderate perfusion defects may be seen in the temporal lobes, frontal lobes and parietal lobes
2.MRI:
a.In one of 7 patients white matter hypertensities (nonspecific) were detected
1.Variegate porphyria is caused by heterozygous mutation in the PPOX gene that maps to chromosome 1q23.3 and encodes the enzyme protoporphyrinogen oxidase
2.Inheritance is autosomal dominant
1.The most prominent manifestation of variegate porphyria is an adult onset of cutaneous blistering skin lesions in sun-exposed areas
2.The lesions:
a.The hands and face are prominently involved
b.The lesions are subepidermal vesicles, bullae and erosions that crust and heal slowly
c.Chronic skin characteristics are milia (small keratin filled cysts), scarring thickening and decreased pigmentation
d.Facial hyperpigmentation and hypertrichosis may also occur
e.Acute neurovisceral symptoms occur after puberty and include:
i.Highly variable attacks that may be similar from episode to episode; not all symptoms occur in a single attack and the acute symptoms may become chronic; attacks are common in women of child-bearing age
ii.Colicky abdominal pain with constipation
iii.Pain in the back, chest and extremities
iv.Seizures
v.Primarily a motor neuropathy that may progress to quadriparesis and respiratory failure
vi.Psychiatric symptoms
vii.Autonomic dysregulation (tachycardia and hypertension)
viii.The disease occurs in a worldwide distribution but is particularly prevalent in South Africa
ix.The homozygous variant of variegate porphyria is manifest by:
1.Photosensitization in early childhood
2.Skeletal hand abnormalities
3.Less frequently: short stature, cognitive dysfunction and seizures
1.The defect is a decreased activity of the enzyme protoporphyrinogen oxidase of approximately 50%
2.Predominant axonal neuropathy
3.Patchy demyelination in the CNS
1.The diagnosis is secured by a combination of blood, urine and fecal tests
2.Biochemically active patients demonstrate:
a.Increased PBG in a spot urine sample and/or increased plasma porphyrins (a distinctive fluorescence peak at 626-628 nm at neutral pH)
3.Increased fecal porphyrins with a predominance of both coproporphyrin III and protoporphyrin IX
4.Molecular genetic delineation of the mutation in the PPOX gene
5.CSF:
a.Most often normal; rarely slightly increased protein
b.EMG:
i.Denervation; some myopathic potentials
ii.CMAPs; small
iii.No demyelinative features
iv.Normal or small SNAPs
1.Fabry’s disease is caused by mutations in the GLA gene that maps to Xq22.1
2.It encodes alpha-galactosidase A
3.Globotriaosylceramide (Gb3) and related glycosphingolipids accumulate in the plasma and tissue cellular lysosomes throughout the body. It is a progressive systemic disease affecting the kidneys, cerebral blood vessels and the heart. It may also manifests primarily as a small-fiber peripheral neuropathy.
1.Children and adolescents present with burning, symmetric pain in the palms of the hands and soles of the feet associated with extremity dysesthesias
2.Patients may suffer recurrent attacks of pain that are described as:
a.Excruciating
b.Lancinating and stabbing
c.Begin distally in the extremities and spread proximally
d.Episodes, (“pain crises”) may occur daily
3.Attacks may be triggered by fever, stress, and physical activity putatively due to an inability to sweat. Rarer triggering events are exposure to cold, rapid humidity change and fatigue
4.A pain crisis may be associated with:
a.Deep muscle aches
b.Joint pain
c.Unexplained fever
d.Increased sedimentation rate
5.Neuropathic pain affects 60-80% of affected boys and 40-60% of girls (usually at a later age than boys)
6.Most adult males and approximately 60-90% of affected females have pain
7.During the course of the illness pain may diminish but rarely becomes more severe
8.Associated signs:
a.Angiokeratoma skin lesions:
i.Appear as clusters of individual punctate, dark red to blue-black angiectases in superficial skin layers; they are flat or slightly raised and do not blanch with pressure
ii.The greatest concentration of lesions is between the umbilicus and knees. Often they are in a “bathing suit distribution”; the oral mucosa, conjunctiva and other mucosae may be involved
iii.The number and size of the lesions increase with age
b.Ocular involvement:
i.A corneal opacity that is termed cornea verticillata (slit lamp) is seen in affected males and most heterozygous females
ii.Lenticular changes, or granular anterior capsular or subcapsular deposits and cataract are seen
iii.Aneurysmal dilatation and tortuosity of both conjunctival and retinal vessels is noted
c.Vascular disease:
i.Cardiac and cerebrovascular disease is present in most males by middle age
d.Renal involvement:
i.Progressive accumulation of glycosphingolipid in the kidney causes azotemia by the third to fifth decade
e.Males and females with the classic phenotype have involvement of gastrointestinal, pulmonary and lymphatic systems
f.Heterozygous females have a less severe course
1.Deficiency of the lysosomal enzyme alpha-galactosidase A causes the systemic accumulation of globotriaosylceramide (Gb3) in the cellular lysosomes of vessels, nerves, tissues and bodily organs
1.Small fiber dysfunction
2.Nerve biopsy:
a.Length dependent neuropathy
b.Reduction of thinly myelinated A-delta fibers (1-4 μ) and unmyelinated C-fibers (1 μ)
c.Autonomic small fiber loss
3.Nerve conduction velocities:
a.Motor and sensory NCV are normal early in the disease course
b.Decreased CMAP amplitudes are seen more often than slow nerve conduction
4.Quantitative sensory testing:
a.Reduction of small fiber modality function:
i.Raised cold and warm detection thresholds
5.Molecular genetic analysis of the GLA gene on Xq22.1 to delineate the mutation
6.Alpha galactosidase can be quantitated (and is decreased) in the plasma, urine and leucocytes
7.Cardiac evaluation:
a.Left ventricular hypertrophy
b.Concentric remodeling of the left ventricle
c.Structural changes in the mitral valve (25% of male patients) and the aortic valve (10%) of male patients
8.Audiograms:
a.Approximately 75% of male patients have high frequency sensorineural hearing loss
9.Renal disease:
a.Manifest in more than 30% of male patients
10. Molecular genetic evaluation is the most reliable method of diagnosing female carriers as many carriers have normal α –Gal A enzyme activity
Chemotherapy-induced peripheral neuropathy affects approximately 30 to 40% of patients that undergo chemotherapy.
The major agents associated with CIPN are:
1.Thalidomide and its analogue lenalidomide
2.Epothilones (ixabepilone)
3.Vinca alkaloids (vincristine and vinblastine)
4.Taxanes (paclitaxel and docetaxel)
5.Proteasome inhibitors (bortezomib)
6.Platinum-based agents that include cisplatin, oxaliplatin, and carboplatin
The occurrence and degree of neuropathy with these agents is determined by the specific drug, the duration of treatment, the quantity administered and if the patient has a neuropathy prior to treatment. In general, the symptoms and signs are sensory but motor and autonomic nerves may be affected. CIPN may be initiated after the first dose and increases with treatment but plateaus by the end of therapy. However, platinum-based drugs demonstrate a “coasting effect” in which sensory modalities may continue for months after completion of treatment. The neuropathy in many patients is irreversible.
Mechanisms for pathogenesis of the neuropathy in CIPN include:
1.Activation of ion channels on pain dorsal root ganglia and spinal dorsal horn neurons that trigger secondary cascades leading to hyperexcitability
2.Opening of MPTP pores on mitochondria that induces intracellular calcium release
3.Activation of protein kinase C
4.Phosphorylation of TRPV receptors
5.Caspase / calpain activation
6.The generation of nitric oxide and free radicals that injures DNA and induces apoptosis of neurons and injures axons
7.Induces inflammatory processes in sensory pain projecting neurons (an inflammatory profile of cytokines and chemokines) that alters pain processing
1.Cisplatin (SP-4-2)-diamminedichloroplatinum(II) causes crosslinking of DNA that results in apoptosis
2.The usual cancers treated with cisplatin are:
a.Sarcomas
b.Some carcinomas
c.Lymphomas
d.Germ cell tumors
e.Gynecological tumors
3.Cisplatins have a molecular affinity for peripheral nerves that are affected due to a less effective nerve-vascular barrier
4.It is a dose-dependent toxic neuropathy usually at a cumulative dose of 225-500 mg/m2
1.The neurotoxic effects can manifest primarily as a sensory neuropathy or ganglionopathy primarily of large fibers
2.Patients develop paresthesias, hyperesthesias, decreased proprioception and vibration sensibility
3.Gait ataxia
4.Pseudoatheitoid movements of the extremities
5.Loss of muscle stretch reflexes in both upper and lower extremities
6.Lhermitte’s sign (approximately 40% of patients)
7.Approximately 2% develop weakness
8.Onset of signs and symptoms may be delayed up to eight weeks after cessation of therapy; deficits may progress for up to 6 months following completion of therapy (coasting)
9.Patients may develop a paradoxical response to cold (perceived as heat)
10. Emerging reports of CNS toxicity with platinum-based chemotherapy include:
a.Encephalopathy
b.Seizures
c.Transient blindness
d.Aphasia
11. Ototoxicity:
a.Hearing loss and tinnitus are frequently encountered
1.Cisplatin causes covalence of DNA that produces intrastrand and interstrand cross-links; formation of these adducts inhibits transcription and replication and produces cell-cycle arrest
2.Inhibition of protein synthesis and axonal transport
3.Nerve biopsy (sural nerve):
a.Large Aα and AΒ fiber loss > than A-delta (1-4μ ) and unmyelinated (1μ ) C-fibers
b.Axonal degeneration with small clusters of regenerating fibers
c.Secondary segmental demyelination
1.QST Increased:
a.Vibratory detection thresholds are decreased early
2.EMG:
a.Low amplitude or unobtainable SNAPs
b.Normal CMAPs and EMG
1.Oxaliplatin-based chemotherapy is the standard treatment for both adjuvant and metastatic colon cancer
2.Neurotoxic effects are a major cause of dose reduction and cessation of its administration
1.Acute neuropathy:
a.Transient and develops either during or just after oxaliplatin infusion
b.Rarely lasts more than 7 days
c.It may be triggered by cold and manifests with:
i.Paresthesias and tingling
ii.Jaw spasm
iii.Limb stiffness
iv.Muscle cramps
d.The incidence of acute neuropathy is 80-98%
2.Chronic neuropathy manifests with:
a.Numbness or tingling of the hands and feet
b.Develops in approximately 10-20% of patients after a cumulative dose of 750-850 mg/m2
c.Signs and symptoms have been reported for 2-5 years after treatment
1.The mechanism of oxaliplatin neuropathy is not known; putatively the acute form is related to chelation of calcium by oxalate, a metabolite of oxaliplatin that leads to sensory neuron hyperexcitability by failure of inhibition of calcium-dependent sodium channels
2.Oxaliplatin slows Na channel inactivation kinetics
3.Cell death of sensory neurons occurs in the DRG
4.Cold hyperalgesia in oxaliplatin has been posited to occur from:
a.TRPA1 expression in small-diameter DRG neurons and by activation of p38 mitogen-activated kinase
1.EMG:
a.Low-amplitude or unobtainable SNAPs
b.Normal CMAPs and needle EMG
1.The neurotoxicity of the antitubulins is different in incidence, clinical manifestations and prognosis for each agent
2.Vincristine is the most neurotoxic and its severity is dose related commencing usually after administration of 4 mg/m2
3.Vinblastine, vinflunine and vinorelbine are less toxic
1.Paresthesias and numbness that at times starts in the fingers prior to the toes
2.Distal extremity weakness occurs in 25-35% of patients
3.Autonomic involvement may cause constipation, urinary retention, impotence and orthostatic hypotension
4.Rarely described are oculomotor palsies, facial and laryngeal weakness and hearing loss
5.A subset of patients develops severe neuropathic extremity pain
6.Symptoms and signs are usually prominent after a cumulative dose of 12mg although neuropathy can develop as early as two weeks after a single 2 mg/m2 dose
7.Approximately 30% of patients have a coasting effect for 1 month after termination of treatment
8.Symptoms and signs often remain for 3 months after treatment
9.Ankle reflexes may be lost prior to changes in sensory modalities
1.Vincristine is a substrate of P-glycoprotein and is metabolized by the cytochrome P-450 (CYP) 3A5 and 3A4 isoforms; CYP3A5 clears 75% of the drug
2.CYP3A5 nonexpressor status is associated with peripheral neuropathy as its dysfunction leads to increased vincristine concentrations
3.Mutation in the centrosomal protein 72 gene that maps to chromosome 5p15.33 has been associated with vincristine neuropathy:
a.The CEP72 gene:
i.Encodes a pericentriolar satellite protein that has a critical role in microtubule organization
ii.Impairs microtubule assembly by binding to tubulin
iii.Disrupts axonal transport
4.Nerve biopsy:
a.Axonal degeneration of both myelinated and unmyelinated fibers
b.Regenerating fiber clusters
c.Some segmental demyelination
1.Neurophysiology:
a.Primarily an axonal sensorimotor peripheral neuropathy
b.Motor and sensory nerve conduction studies demonstrate reduced amplitudes, normal or only slightly prolonged distal latencies and slowed conduction velocities
c.Fibrillation and positive sharp waves may be demonstrated in distal muscles
2.QST:
a.Decreased vibratory detection thresholds are decreased early
1.Vinorelbine is a semisynthetic vinca alkaloid that is primarily used in the treatment of non-small-cell lung cancer. It is also used off label for metastatic breast cancer and rhabdomyosarcoma
2.It causes a dose-dependent peripheral neuropathy in 20-50% of patients
1.A progressive and often irreversible tingling numbness
2.A subset of patients have intense distal extremity neuropathic pain
3.Hypersensitivity to cold
4.Usually begins in the hands and feet with proximal progression
5.Autonomic symptomatology occurs but is not as severe as that which occurs with vincristine
6.A severe neuropathy only occurs in approximately 1% of patients
7.Motor weakness may occur after 3-6 months of treatment
8.Loss of ankle reflexes occurs after approximately 12 cycles
1.Binds to tubulin which inhibits mitotic microtubule polymerization
1.EMG/ NCV:
a.Dose-dependent decrease of SNAP and CMAP amplitudes
b.Normal distal latencies and conduction velocities
1.Paclitaxel and docetaxel are used either alone or in combination with other agents in the treatment of breast, ovarian, lung and other cancers
2.Paclitaxel may be more neurotoxic than docetaxel
1.Sensory symptoms are most common and are dose dependent
2.A mild neuropathy develops in up to 85% of patients after 3 to 7 cycles of treatment with Taxol with administration of 135-200 mg/m2
3.A severe neuropathy may occur in 2% of patients at this dosage
4.Doses between 250 and 350 mg/m2 may cause symptoms after the first or second cycles at times within 24 hours of administration
5.Approximately 70% of patients develop a neuropathy after high dose regimes
6.Both paclitaxel and docetaxel cause:
a.Paresthesias and dysesthetic pain in the feet and hands
b.A predominant loss of vibration and proprioceptive modalities > pain and temperature (small fiber)
c.Gait unsteadiness
d.Sensory ataxia
e.Weakness is usually minimal although motor neuropathy has been described; if weakness occurs it may be proximal
f.A severe neuropathy may develop if the patient has a preexisting neuropathy or has been treated with other neurotoxic agents (usually occurs with a cumulative dose >1500 mg/m2)
g.Taxane acute pain syndrome (TAPS) is characterized by:
i.Myalgias and arthralgias that start 1-3 days and last 5-7 days after taxane-based chemotherapy
1.Taxanes may affect the neuronal cell body, the axon or both concomitantly
2.Taxol and taxotere increase tubulin polymerization that causes aggregation and an accumulation of abnormal bundles of microtubules in the DRG, axons and Schwann cells which putatively interfere with axonal transport
3.Nerve biopsy (sural nerve):
a.Loss of large myelinated fibers
b.Axonal degeneration with secondary demyelination and remyelination
c.Electron microscopy:
i.Tubular and membranous structures within axons
d.Some small fiber involvement
e.Small clusters of regenerating fibers
1.Electrophysiology:
a.Nerve conduction studies:
i.Reduced SNAP and CMAP amplitudes (correlate with dosage)
ii.Normal distal latencies and conduction velocities; rarely demyelinating features (slowed conduction velocities are demonstrated)
iii.Fibrillation potentials may occur in distal extremity muscles
2.QST
a.Vibratory detection thresholds are more often impaired than thermal thresholds
1.Primarily used for locally advanced or metastatic cancers:
a.Breast cancer
b.Head and neck cancer
c.Gastric cancer
d.Hormone-refractory prostate cancer
e.Non-small cell lung cancer
2.Docetaxel may be twice as potent as paclitaxel but has comparable efficacy
1.Causes a dose-dependent primarily sensory neuropathy that is usually less severe than that which occurs with Taxol
2.Pain in the hands and feet
3.Lhermitte’s sign may be present
4.Large fiber modalities of vibration are more affected than small fiber modalities
5.Reduced or absent ankle reflexes
6.Mild proximal and distal weakness occurs in 5-19% of patients
7.“Coasting” may occur for several months after treatment although many patients improve 1-2 months fallowing cessation of their protocols
1.Binds to microtubules with high affinity which stabilizes them and prevents depolymerization / disassembly in the absence of GTP
2.Failure of disassembly causes a decrease in free tubulin needed for microtubule formation which causes inhibition of mitotic cell division between metaphase and anaphase
3.Microtubule accumulation intracellularly initiates apoptosis
4.Sensory nerve biopsy:
a.Loss of large myelinated fibers
b.Scattered fibers with axonal degeneration
1.EMG/ NCV:
a.Diminished amplitude of motor and sensory nerve amplitudes
b.Mild slowing of conduction velocities
1.Epothilones are microtubule stabilizing agents that are used in various types of refractory treatment-resistant cancer
2.Ixabelone is primarily used
1.Cumulative dose and possible preexisting neuropathy are risk factors
2.Primarily a sensory distal peripheral neuropathy similar to the taxanes
1.Disruption of microtubules of the mitotic spindle
2.Interference with axon transport
1.EMG/ NCV:
a.Axonal dose-dependent neuropathy
1.Suramin is a hexasulfonated naphthylurea
2.It is used either alone or in combination with other chemotherapeutic protocols for the treatment of hormone-resistant or metastatic prostate cancer
1.It causes a peripheral neuropathy in 25 to 90% of patients
2.Neurotoxicity is the dose-limiting side effect
3.A distal axonopathy is the more common neuropathy and is characterized by:
a.Distal numbness and paresthesia
b.Decreased light touch, pain and vibration sensibility
c.Mild weakness of the distal extremities (toe extensors)
d.Decreased ankle reflexes
e.This form of neuropathy is reversible with cessation of treatment
4.Subacute sensorimotor demyelinating neuropathy:
a.Is more severe than the axonal neuropathy and occurs in 10-20% of patients after 1-5 months of treatment
b.It occurs when a peak plasma concentration of over 300 μg/L exposure to > 200 μg/L for 25 days per month or if a cumulative dose of 40,000 μg/L is attained
c.Numbness and paresthesias of the distal extremities
d.A symmetrical proximal > distal muscle weakness
e.Decreased or absent reflexes in both upper and lower extremities
f.The weakness can involve respiratory muscles and approximately 25% of patients require mechanical ventilation
g.“Coasting” may occur for approximately 1 month following cessation of therapy
h.Recovery occurs slowly and often there is residual weakness and numbness
1.Suramin is pleiotropic and causes:
a.Inhibition of apoptosis
b.Suppression of proinflammatory cytokines
c.Inactivates myofibroblasts
d.Stimulates proliferation of renal epithelial cells
2.Action on nerves is not known. Suggested mechanisms include:
a.Interference with neurotrophic factor interaction with their receptors
b.Lysosomal dysfunction
c.Possible immune-mediated demyelination
3.Sural nerve biopsy:
a.Patients with subacute demyelinating polyradiculoneuropathy:
i.Loss of large and small myelinated fibers
ii.Secondary axonal degeneration
iii.Epi and endoneurial mononuclear inflammatory infiltrates
4.Accumulation of glycolipid lysosomal inclusions have been demonstrated in animal models
1.Elevated CSF protein may be seen in the subacute demyelinating neuropathy
2.Patients with axonal neuropathy:
a.EMG/ NCV:
i.Decreased amplitudes of SNAPs and CMAPs
ii.Minimal abnormalities of distal latencies and conduction velocities
3.Patients with the subacute sensorimotor polyradiculoneuropathy:
a.EMG/ NCV:
i.Prolonged distal latencies and F-waves
ii.Slowed conduction velocities
iii.Temporal dispersion
iv.Conduction block
4.QST:
a.Increased vibratory and cooling detection thresholds
5.Needle EMG:
a.Decreased recruitment of MUAPs in proximal and distal muscles
b.Occasional fibrillation potentials
1.Bortezomid is a polycyclic derivative of boronic acid that inhibits the mammalian 265 proteasome
2.Additional actions include:
a.It suppresses secretion of bone marrow cytokines
b.Increases oxidative stress
1.Neuropathy that is emergent or worsening of a preexisting neuropathy occurs in approximately 35% of patients in myeloma treatment trials
2.1 to 1.3 mg/m2 appears to be the neurotoxic dose; the risk of neuropathy is dose dependent and approximately 50% of patients will be affected at a cumulative dose of 30 mg/m2
3.Sensory complaints are burning dysesthesia, paresthesias, and numbness in a length dependent manner
4.Autonomic dysfunction occurs that includes postural hypotension
5.Signs and symptoms usually improve in 3 to 4 months
1.The boron atom in bortezomib binds the catalytic site of the 265 proteasome
2.Bortezomib causes a rapid change in the levels of intracellular peptides that may contribute to its biological effects
3.Increases oxidative stress
4.Suppresses bone marrow secretion of cytokines
5.One patient has been described with spongy degeneration of the DRGs
1.NCS:
a.Consistent with an axonal sensory neuropathy
2.QST:
a.Early small fiber parameters are affected
b.Increased temperature detection thresholds
1.Belongs to the topoisomerase inhibitor class of drugs
2.It is used to treat:
a.Kaposi’s sarcoma
b.Ewing’s sarcoma
c.Lung cancer
d.Testicular cancer
e.Lymphoma
f.Non-lymphocytic leukemia
g.Glioblastoma multiforma
3.It is also administered:
a.In combination with bleomycin for testicular cancer
b.As one of the conditioning agents prior to bone marrow or blood stem cell transplantation
c.It is a semisynthetic derivative of podophyllotoxin
1.Causes a moderate-to-severe sensory axonal neuropathy or ganglionopathy in approximately 4 to 10% of patients
2.A subset of patients develop an autonomic neuropathy characterized by orthostatic hypotension and gastroparesis
1.Etoposide forms a ternary complex with DNA and the topoisomerase 11 enzyme
a.The complex prevents re-ligation of DNA strands and strand breaks
b.Inhibits microtubule function
1.NCS:
a.Low amplitude SNAPs and CMAPs
1.Ifosfamide is primarily used in the treatment of bone and soft tissue sarcomas in children and young adults
2.Ifosfamide is an alkylating agent (a cyclophosphamide analog)
1.The cumulative dose for toxicity is 14g/m2
2.Peripheral neuropathy:
a.Patients develop numbness and painful paresthesias that begin in the hands and feet approximately 10-14 days after cessation of treatment
b.Rarely the neuropathy begins in the hands
c.The neuropathy gradually resolves
d.Encephalopathy:
i.Occurs in approximately 50% of patients
ii.Putatively mediated by chloracetaldehyde (a break down product of ifosfamide)
iii.Patients may be just confused but others have developed delirium, status epilepticus and coma
iv.Methylene blue shortens the duration of the encephalopathy and may be prophylactic
1.Ifosfamide is an alkylating agent that is a prodrug which requires activation by hepatic microsomal enzymes to ifosfamide mustard
2.It alkylates DNA which forms DNA-DNA cross-links that inhibit DNA synthesis
1.NCS/EMG:
a.Axonal neuropathy
1.Is primarily used in the treatment of acute myeloid leukemia and non-Hodgkin lymphoma
2.Cytosine arabinoside is similar enough to human cytosine deoxyribose to be incorporated into human DNA which kills the cell
3.The drug alters the sugar component of nucleosides
4.Neuropathy may occur with cumulative doses that range from 60mg/m2 to 36 g/m2
1.The neuropathy can begin within hours to weeks following treatment
2.A sensorimotor polyneuropathy occurs that resembles GBS after administration of high doses
3.Respiratory failure has been described with high dose therapy
4.A length-dependent sensory neuropathy occurs at low to intermediate doses
1.Sural nerve biopsy:
a.Demyelination or axonal degeneration
b.Suggested mechanisms of action include:
i.Immune dysregulation
ii.Decreased protein synthesis that is necessary for myelin, axonal structure or transport
c.High dose cytarabine has been associated with cerebral, cerebellar, spinal cord dysfunction and ocular pathology
d.Cytosine arabinoside:
i.It is rapidly converted into cytosine arabinoside triphosphate which damages DNA in the S phase of the cell cycle (during DNA synthesis)
ii.Inhibits both DNA and RNA polymerases and nucleotide reductases
1.Patients with GBS presentation:
a.Demonstrate increased CSF protein
b.EMG and NCS:
i.Demonstrate an acquired demyelinating sensorimotor polyneuropathy
ii.Primarily axonal neuropathy
1.Thalidomide is primarily used in the treatment of multiple myeloma, Waldenstrom’s macroglobulinemia, acute myeloid leukemia
2.Lenalidomide (alpha-3-amino-phthalimido glutarimide) is an analogue of thalidomide with less toxicity
1.The peripheral neuropathy is frequently dose limiting
2.The usual cumulative dose that causes neuropathy is 7 grams; less than 10% of patients with a lesser dose are symptomatic
3.The usual symptoms are numbness, painful tingling and burning pain in the feet and hands (lenalidomide is similar but less toxic)
4.Muscle weakness occurs and is most prominent distally
5.Generalized hypo or areflexia
6.Large fiber modalities of sensation (12-20μ) for vibration and proprioception are more effected than small fiber modalities
1.Sural nerve biopsy:
a.Loss of large-diameter myelinated fibers; axonal degeneration
b.Loss of DRG cells
c.Thalidomide has pleiotropic effects:
i.Anti-angiogenic
ii.Anti-oxidative stress
iii.Inhibits TNF-α, IL-6, IL-10, and IL-12
iv.Modulates the production of IFN-γ
v.Decreases the production of IL-2, Il-4, and IL-5 by immune cells
vi.Decreases NF-KB and COX-2 activity
vii.Thalidomide binds cereblon which is a ubiquitin ligase substrate adapter protein and may be causative in its teratogenicity
1.Nerve conduction studies:
a.Reduced amplitudes or absence of SNAPs
b.Usually preserved conduction velocities particularly of motor nerves
1.Symptoms and signs usually develop during treatment, but may progress (‘coasting’) for 2 to 6 months following its cessation:
a.Approximately 20% of patients may be affected (based on a study of patients treated for testicular cancer 23 to 33 years following treatment)
b.A similar study revealed that 28% of patients had an asymptomatic neuropathy while 38% of patients were symptomatic after a median follow-up of 15 years
c.Other symptoms and signs include:
i.Persisting taste and smell dysfunction
ii.Oto and vestibular abnormalities
iii.Raynaud’s phenomenon
iv.Mobility problems in older patients
v.Persistent neuropathic pain
1.Reversible in approximately 80% of patients; may completely resolve in 40% of patients at 6-8 months
1.Frequently used in the treatment of gastrointestinal cancer
2.92% of patients develop a sensory neuropathy which resolves in approximately 9 months
3.Dysesthesia and cold induced pain may be persistent
1.Approximately 15% persistent neuropathy at 6 months; at 48 months, 23% of patients have residual neuropathy
1.The neuropathy is often reversible after cessation of therapy. The median duration of paresthesia and weakness is 3 months
2.Cramps occur in the small muscles of the feet > hands
1.The incidence of neuropathy varies from 25% to 83% and is dose dependent
2.Approximately 15% of patients interrupt therapy due to neurotoxicity
3.The neuropathy is often irreversible after a cumulative dose of 20 grams
1.Signs and symptoms of neuropathy improve or resolve 3-4 months following treatment
2.Has been utilized as a radiotherapy sensitizer and for bladder cancer
2.Patients get painful paresthesias primarily of the feet
3.Loss of both large and small fiber modalities
4.Distal muscle weakness occurs in a length dependent manner
5.Reflexes are preserved
6.The neuropathy occurs in approximately 40% of patients and 80% of patients have residual signs and symptoms three years after cessation of treatment
1.Sural nerve biopsy:
a.Decreased large myelinated fibers with axonal degeneration and swellings
b.Segmental demyelination and remyelination
2.Electron microscopy
a.Accumulation of neurofilaments with axon swelling
3.Misonidazole has high electron affinity, induces the formation of free radicals, and depletes radioprotective thiols that sensitize hypoxic cells to the cytotoxic effects of ionizing irradiation. The mechanism of action in producing neuropathy has not been established.
1.Electrophysiology:
a.Low amplitude or unobtainable SNAPs with slightly reduced CMAPs
2.It is a synthetic 5-nitro-imidazole
1.Painful extremity paresthesias
2.Loss of both small and large fiber sensory modalities
3.Rarely distal weakness in a length dependent manner
4.Metallic taste
5.Central neurological characteristics:
a.Seizures
b.Diffuse encephalopathy
c.Acute and chronic cerebellar toxicity
1.Sural nerve biopsy:
a.Axonal degeneration
2.It inhibits nucleic acid synthesis by disrupting DNA of mitochondrial cells
1.Electrophysiology
a.Low-amplitude or unobtainable SNAPs with normal CMAPs
1.Amiodarone is a class III antiarrhythmic drug used for both ventricular and atrial arrhythmias; it is also indicated for recurrent ventricular fibrillation or hemodynamically-unstable ventricular tachycardia
1.Patients develop a neuromyopathy similar to that induced by chloroquine
2.Patients develop distal extremity sensory loss manifest by tingling and burning pain
3.Severe proximal and distal muscle weakness may develop which is worse in the legs than the arms
4.Two to three years of use is required for the induction of the neuromyopathy
5.Reduced sensation to all modalities
6.Decreased or absent muscle stretch reflexes
7.Associated medical conditions include:
a.Tremor
b.Thyroid dysfunction
c.Pulmonary fibrosis
d.Parotid gland hypertrophy
e.Corneal micro deposits
f.Light-sensitive blue-gray skin discoloration
1.Sural nerve biopsy:
a.Segmental demyelination and axonal degeneration
2.Electron microscopy:
a.Lamellar or dense inclusions in Schwann cells, pericytes and endothelial cells
3.Muscle biopsy:
a.Electron microscopy:
i.Autophagic vacuoles with myeloid and dense inclusions
ii.Neurogenic atrophy in distal muscles
4.In immortalized adult rat Schwann cells amiodarone caused:
a.Accumulation of phospholipids and neutral lipids
b.Upregulation of the expression of gangliosides
c.Increased oxidative stress
d.Impaired lysosomal degradation in Schwann cells
1.Electrophysiology (EMG/ NCV):
a.Low-amplitude or unobtainable SNAP
b.Normal or reduced CMAP amplitudes
c.Irritable and myopathic MUAPs in proximal muscles of patients with myopathy
d.Needle EMG demonstrates distal denervation with fibrillations, positive sharp waves and occasional myotonic discharges
e.Sensory NCS:
i.Moderately slow conduction velocities and prolonged distal latencies
1.Disulfiram is characteristically used as a second-line agent for treating chronic alcoholism
2.Alcohol is metabolized by alcohol dehydrogenase to acetaldehyde, which is then metabolized by aldehyde dehydrogenase to acetic acid and excreted
3.Disulfiram inhibits aldehyde dehydrogenase which increases the serum concentration of acetaldehyde to cause symptoms of a “hangover”
1.The onset of disulfiram neuropathy is over weeks rather than over months which is characteristic of alcohol
2.Muscle tenderness
3.Hyperhidrosis of distal limbs
4.A subset of patients have painful lower extremity burning paresthesias
5.Numbness and pain in the soles of the feet that then progresses in a length-dependent pattern
6.Weakness of lower extremity distal musculature
7.Depressed ankle jerks
8.Loss of both large and small fiber sensory modalities below the knees
1.Sural nerve biopsy:
a.Loss of large-diameter myelinated fibers is predominate and although there may be significant concomitant loss of small-diameter fibers
b.Axonal degeneration
c.Segmental demyelination
d.Electron microscopy:
i.Axonal swelling due to the accumulation of neurofilament debris
2.Possible effects from carbon disulfide that is a metabolite of disulfiram metabolism in the liver
3.Degeneration of DRG
1.Electrophysiology (EMG/ NCV):
a.Low amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes
b.Needle EMG:
i.Positive sharp waves and fibrillation potentials in distal muscles
ii.Decreased recruitment of neurogenic MUAPs
2.It is odorless and tasteless; in the past was widely used as a rodenticide
3.It is primarily used in the electronic industry, pharmaceutical industry and glass manufacturing
4.Exposure can occur by the respiratory route, skin absorption or oral intake
1.Neurologic signs and symptoms usually start within 2-5 days; rarely patients may be symptomatic neurologically < 24 hours post exposure
2.Pain and paresthesias of the hands and lower extremities especially the soles of the feet
3.Painful length-dependent sensory symptoms
4.Distal muscle weakness more severe in the legs than arms
5.Less frequently:
a.Ataxia
b.Tremor
c.Athetosis
d.Cranial nerve palsies
e.Headache
f.Seizures
g.Insomnia
h.Coma
i.Autonomic dysfunction
j.Neuropsychiatric manifestations
k.Associated medical conditions:
i.Gastrointestinal symptoms occur within the first 3-4 hours that include abdominal pain, nausea, vomiting, diarrhea or constipation
ii.Ocular dysfunction includes abnormal color vision, diplopia and decreased visual acuity from optic neuropathy
iii.The first cutaneous signs are scaling of the palms and soles with an acneiform or pustular rash of the face
iv.During 2-3 weeks, following exposure there is diffuse alopecia. The scalp, temporal parts of the eye brows, eyelashes and limbs
v.Mees lines occur in the nail plate (transverse white lines)
vi.Tachycardia, hypertension and pleuritic chest pain occur
2.Chromatolytic changes in anterior horn cells
3.Experimental studies demonstrate large intra-axonal vacuoles at the nodes of Ranvier
1.Thallium can be recovered in the hair, nails, feces, saliva, and urine. A 24 hour thallium concentration evaluation by atomic absorption spectrometry is standard and should be <5 meq/L
2.EMG/ NCV:
a.Low-amplitude or unobtainable SNAPs with normal or decreased CMAP amplitudes
1.Arsenicals are still used in some agricultural pesticides
2.Chronic toxicity from ingestion or inhalation may be occupational or environmental (wells from water sheds near old mines)
3.Acute toxicity occurs with accidental ingestion, suicide attempts and intentional poisoning
4.Arsenic may be in Chinese herbal balls and Korean herbal medications
5.Arsenic is used to treat and preserve lumber, in wallpaper, to strengthen lead and in the glassmaking industry
1.Acute intoxication:
a.A burning sensation in the mouth and throat
b.Severe abdominal pain, cramping, diarrhea and vomiting
c.Breath and stool smells like garlic
d.Vertigo is followed by delirium, convulsions and coma
e.Circulatory collapse followed by hepatic and renal failure
f.Severe acute axonal neuropathy has followed treatment with arsenic trioxide for acute promyelocytic leukemia
2.Subacute arsenic toxicity:
a.Abdominal pain
b.A length dependent primarily sensory neuropathy characterized by burning pain and paresthesia
c.Generalized muscle weakness
d.Autonomic dysregulation
e.A Guillain-Barré syndrome presentation
1.Enzyme systems with sulfhydryl groups are particularly vulnerable to arsenicals
2.Pyruvate dehydrogenase may be inhibited by conversion of the cofactor lipoic acid, which contains a dithiol group, to lipoate arsenate. This reaction inhibits the conversion of pyruvate to acetyl CoA which inhibits the Krebs cycle
3.Sural nerve biopsy:
a.Primarily axonal degeneration
1.Patients with long-term exposure develop a microcytic, hypochromic anemia; eosinophilia and neutropenia may be concomitant
2.A 24 hour urine collection for total arsenic is diagnostic; it is also stored in hair and fingernails; the usual dose of arsenic excreted in the urine of symptomatic patients is 100-400 mcg/ 24 hours
3.EMG/ NCV:
a.Low amplitude or unobtainable SNAPs with normal or reduced CMAPs
b.Demyelinating features
c.Prolonged distal latencies
d.Slow conduction velocities
1.Nitrofurantoin is an antibiotic primarily utilized for urinary tract infections
1.Patients most often develop sensory complaints of numbness and painful paresthesias
2.Motor weakness may be severe and lead to quadriparesis
3.Elderly patients and those with poor renal function are at greatest risk
4.There is decreased sensation to all modalities in a length-dependent manner
5.Distal muscle weakness
6.Loss or decreased muscle stretch reflexes
1.Axonal degeneration
2.Degeneration of DRG and anterior horn cells
3.Skin biopsy (1 patient):
a.Clustered terminal nerve swellings without nerve terminal degeneration
1.EMG/ NCV:
a.Low amplitude or unobtainable SNAPs
b.Normal or reduced CMAP amplitude
c.Normal conduction velocities in the patient with small fiber presentation
1.Isonicotinylhydrazide (INH) is an antibiotic used as a first-line drug for the treatment and prevention of latent and active tubercular infections
2.It is utilized for typical and atypical mycobacterium (M. kansasii and M. xenopi)
3.INH blocks the formation of mycolic acids that are required for synthesis of the mycobacterial cell wall
1.Approximately 20% of patients taking >6 mg/kg/d develop a peripheral neuropathy
2.The standard dose of 3-5 mg/kg/d causes neuropathy in approximately 2% of patients
3.Elderly, malnourished patients and “slow acetylators” are at risk for peripheral neuropathy
4.The neuropathy usually develops after 6 months of therapy but has been described within weeks in patients taking high doses
5.Patients present with numbness and tingling of their hands and feet
6.During continued therapy, painful dysesthesia may appear in a length-dependent manner along with distal weakness
7.Examination reveals loss of all sensory modalities, distal muscle weakness and atrophy
8.Rare sensory ataxia
9.Generalized reduction or loss of muscle stretch reflexes
1.Sural nerve biopsy:
a.Loss of both myelinated and unmyelinated nerve fibers
b.Axonal degeneration
2.Degeneration of the dorsal columns
3.INH causes pyridoxine deficiency by inhibiting pyridoxal phosphatase
1.EMG/ NCV:
a.Electrophysiology
i.Decreased or unobtainable SNAPs with less severe involvement of CMAPs
b)Didanosine (dideoxyinosine; ddI)
c)Stavudine (d4T)
d)Lamivudine (3Tc)
e)Antiviral nucleoside reverse transcriptase inhibitors
f)The above agents are all used in the treatment of HIV patients
1.At doses greater than 0.18mg/kg/d ddC causes neuropathy
2.DdC is a nucleoside analog reverse transcriptase; it is less potent than some other reverse transcriptase inhibitors (RTIs)
3.It is an analog of pyrimidine, is phosphorylated in T cells and other HIV target cells to its active triphosphate form ddCTP. This metabolite is a substrate for HIV reverse transcriptase and is incorporated into viral DNA. This terminates chain elongation due to lack of the hydroxyl group. Its activity is limited to retroviruses
1.On doses of 0.03 mg/kg/d approximately 1/3 of patients develop a peripheral neuropathy within 1 week to 1 year (mean of 16 weeks) from onset of therapy
2.Patients develop a length dependent extremity hyperpathia
3.Small fiber modality decrease of pinprick and temperature sensation are more affected than large fiber vibration and position sense
4.Mild weakness of intrinsic foot and ankle musculature occurs
5.Decreased muscle stretch reflexes at the ankle
6.The “coasting affect” may be seen 2-3 weeks following cessation of therapy
1.Nucleoside reverse transcription inhibitors:
a.Have varying affinities for human mitochondrial DNA polymerase γ (POLG) which is the primary enzyme for mitochondrial replication
b.Loss of mitochondrial replication causes:
i.Impaired oxidative phosphorylation
ii.Increased production of free radicals
iii.Oxidative stress
iv.Specific NRTIs are more neurotoxic than others
1.ddC is more toxic than ddI or d4T and the combination of ddI/d4T
2.The differences in neurotoxicity may be related to their affinities for specific thymidine kinase isoforms
1.EMG/ NCV:
a.Reduced or absent SNAPs
1.Lyme disease is due to infection with Borrelia burgdorferi that is transmitted by the deer tick Ixodes dammini
2.It requires 12 to 24 hours of tick attachment to infect the human host
3.The three stages of Lyme disease are:
a.Early infection characterized by localized erythema migrans
b.Disseminated infection associated with systemic symptoms that include:
i.Fever and chills
ii.Localized adenopathy
iii.Fatigue
iv.Myalgia and headache
v.Neck and back pain
vi.Pericarditis and heart block
vii.Inflammatory changes of large and small joints
viii.Erythema migrans in other parts of the body
c.Neurologic complications develop during second and third stages of the infection
1.Facial palsy may be bilateral
2.The neuropathy may be asymmetric
3.Approximately 50% of patients develop numbness, paresthesias, cramps and weakness distally in the extremities
4.Greater loss of vibration and proprioception than small fiber modalities
5.Muscle stretch reflexes are depressed
6.In addition to peripheral neuropathy (length dependent) patients may have:
a.Mononeuropathies
b.Mononeuropathy multiplex
c.Painful radiculopathy
d.Plexopathies
7.Associated neurologic manifestations include:
a.Encephalitis / meningitis
b.Myelitis
c.Cranial neuropathies (VIIth nerve palsy most commonly)
d.An inflammatory myopathy
e.Acrodermatitis chromica atrophicans, a bluish discoloration of the skin, along with continued joint destruction may be seen late in the disease course
1.Sural nerve biopsy:
a.Perivascular infiltrates of plasma cells and lymphocytes around small endoneurial, perineurial and epineurial small blood vessels
b.Experimental studies in Rhesus DRG explants exposed to live B burgdorferi organisms reveal:
i.CCL2 and IL-6 in sensory neurons, satellite glial cells and Schwann cells
ii.IL-8 in satellite glial cells and Schwann cells
iii.Neuronal apoptosis
iv.B. Burgdorferi is internalized through the endo-lysosomal pathway that activates intracellular pathogen recognition receptors
1.Immunofluorescent or enzyme-linked immunosorbent assays may be an initial screen
2.Western blot assays are utilized to confirm a positive enzyme-linked immunosorbent assay
3.CSF evaluation in patients with polyradiculitis, cranial nerve and central nervous system manifestation demonstrates:
a.Lymphocytic pleocytosis
b.Mild to moderately increased protein
4.EMG/ NCV:
a.Dependent on the specific peripheral nerve involvement
i.A primary axonopathy in peripheral nerves
ii.Mononeuropathy or mononeuropathy multiplex
1.Reduced CMAPs and SNAPs
2.Absent H-reflexes
iii.Facial palsy:
1.Decreased facial nerve CMAPs
2.Abnormal blink reflexes
iv.Electrophysiological characteristics are often asymmetric
v.Needle EMG:
1.Increased insertional and spontaneous activity
2.Positive sharp waves and fibrillation potentials
3.Decreased recruitment of MUAPs that have neurogenic characteristics
1.Approximately 20% of patients that are affected by HIV develop a painful neuropathy from the infection itself or other associated viral infections such as CMV
2.A significant number of patients develop neuropathy from the neurotoxic effects of nucleoside analogs:
a.Spontaneous pain that may be lancinating
b.Associated autonomic neuropathy
c.Mechanical allodynia
1.Distal Symmetric Polyneuropathy:
a.DSP is the most common painful neuropathy associated with HIV infection and AIDs
b.Numbness and painful paresthesias affect the distal legs and arms
c.There is reduced sensibility to all modalities
d.Mild distal extremity weakness is seen early in the infection; proximal leg and distal arm weakness is a feature of late disease
e.Muscle stretch reflexes are decreased in the ankles but retained at the knees and in the upper extremities
1.Sural nerve biopsy:
a.Loss of both myelinated and unmyelinated axons
b.Loss of neurons in the DRG and secondary degeneration of the posterior columns
c.Perivascular inflammation composed of macrophages, T lymphocytes and increased expression of proinflammatory cytokines
d.Skin biopsy:
i.Decreased density of small myelinated (A-delta fibers) epidermal fibers is demonstrated
1.CMV Infection:
a.An acute progressive lumbosacral polyradiculoneuropathy may be seen in severely ill AIDs patients
b.CD4+ count is often less than 50 cells/mm3
c.Patients present with severe radicular pain in the lower extremities
d.Asymmetric leg weakness
e.Loss of perineal sensation associated with bowel and bladder incontinence
f.Less frequently the arms and cranial nerves may be affected
g.Decreased or absent muscle stretch reflexes occur in the lower extremities
h.Babinski sign may be demonstrated if there is an associated CMV transverse myelitis
i.CMV associated retinitis may be associated
1.Ventral and dorsal root inflammation is evident most severely in the lumbosacral areas
2.Less frequently there is involvement of cranial nerve roots as they exit the brainstem with associated myelitis
3.CMV inclusions are seen in endothelial cells and macrophages in nerve roots
4.Neurons may be damaged by CMV directly or by ischemia from a secondary vasculitis
1.CSF:
a.A neutrophilic pleocytosis that is associated with a low glucose and high protein
b.Positive CMV cultures can be obtained from the CSF, blood and urine
2.Electrodiagnostic studies:
a.NCS:
i.Asymmetric decreased amplitudes of SNAPs and CMAPs
ii.EMG (needle):
1.Active denervation in the muscles innervated by the affected roots
1.Infectious causes include:
a.CMV
b.Herpes simplex virus (1 and 2)
c.Varicella zoster virus
d.Mycobacterium tuberculosis
1.Multiple mononeuropathies are seen in patients with HIV infection associated with AIDS.
a.Patients present with paresthesias and pain, numbness, weakness and loss of reflexes in the territory of the affected nerve
1.Axonal neuropathy that may be caused by a necrotizing vasculitis or perivascular inflammation
2.Putative deposition of HIV antigen-antibody complexes on blood vessel walls
3.Associated hepatitis B and C infection or CMV involvement
1.CSF:
a.Mononuclear pleocytosis
b.Elevated protein
2.EMG/ NCV:
a.NCS and EMG evaluation is compatible with vasculitis
1.Herpes varicella zoster (HVZ) causes peripheral neuropathy from
2.Reactivation of latent virus or a primary infection. Severe disseminated zoster occurs in immunosuppressed patients while dermal zoster is associated with reactivation in later life
3.The reactivation rate is approximately 33% in seropositive individuals over age 50
1.Approximately 2/3 of infections in adults are manifested as dermal zoster
2.Severe pain and paresthesias develop in a dermatomal distribution:
a.Thoracic dermatomes are affected in 50% of patients
b.Trigeminal distributions in 18%
c.Cervical dermatomes in 14% of patients
3.25% of patients develop postherpetic neuralgia
4.The rash develops approximately 1-2 weeks following dermatomal pain. It is vesicular and appears in the affected dermatome
5.Weakness in the affected roots occurs in 5-30% of patients which develops within 2 weeks of the skin eruption but can vary from hours to a month
6.Segmental zoster paresis occurs:
a.Involvement of thoracic dermatomes may cause abdominal hernias
b.Unilateral phrenic nerve involvement with diaphragmatic paralysis has been described
7.CNS involvement:
a.Encephalitis (particularly with V1 involvement)
b.Meningitis
c.Transverse myelitis
d.MCA and carotid artery stroke
8.Neurological complications occasionally occur without a rash
9.Postherpetic neuralgia:
a.Pain in affected dermatome for more than 3 months after the skin lesions have healed
b.Pain is seen in 9 to 15% of patients after one month and in approximately 2 to 5% of patients at one year
c.The pain may be spontaneous and burning, stimulus evoked or lancinating
1.Evaluation of spinal nerves:
a.Axonal degeneration with secondary demyelination
b.Destruction of DRG neurons
c.Secondary degeneration of the posterior columns
2.Following primary infection, a latent infection is established in neurons of the DRG:
a.Latent viral DNA is in an “end-less’ state such that the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers from which viral gene transcription is restricted
b.Upon reactivation the virus travels down the sensory nerves to involve both motor and cutaneous innervations
1.CSF:
a.Elevated protein with or without pleocytosis
b.Polymerase chain reaction to confirm the diagnosis
c.Electrodiagnostic studies:
i.NCS
1.Decreased or absent SNAPs in affected nerves
2.Normal or decreased CMAP amplitudes
ii.Needle EMG:
1.Positive sharp waves and fibrillation potentials
2.Neurogenic like MUAPs recruitment in affected muscles
1.HSV-1 infection most commonly causes oral mucosal infection and facial skin lesions
2.HSV-2 causes genital mucosal ulceration; HSV-2 patients may not develop clinical disease but shed virus from the genital tract intermittently
3.HSV becomes latent in sensory ganglia following infection that is permanent
1.Both HSV1 and HSV-2 may cause meningitis
2.HSV-1 has been described in a patient with:
a.Atypical lumbosacral pain
b.Weakness of motor roots L4-S1
3.HSV-2 infection may cause:
a.Weakness in L4-S2-S4 dermatomes
b.Paresis of the urinary and anal sphincters
c.Paresthesia and pain in the buttocks and lower extremities
d.Patients may develop peripheral signs and symptoms after herpetic meningitis and encephalitis have cleared
e.Shooting lancinating pain may occur prior to blister formation with genital HSV-2 infection (in genital areas)
f.The first episode of infection may be the most severe and can be associated with fever, muscle pain, swollen lymph nodes
g.Associated neurologic conditions:
i.Herpes keratitis
ii.Herpes encephalitis
iii.Severe neurologic complications occur in immunosuppressed patients
1.Herpes is contracted through direct contact with an active lesion or body fluid
2.Virus gains entry into neurons by entry receptors that include nectin, HVEM and 3-0 sulfated heparin sulfate
3.Herpetic CNS lesions:
a.Intense hemorrhagic necrosis of the inferior and medial temporal lobes
b.Lesions may also occur in the cingulate gyri and insular cortex
c.Acute stage demonstrates intranuclear eosinophilic inclusions in neurons and glial cells
1.CSF:
a.A lymphocytic pleocytosis of 10-200 cells/mm3
b.RBCs may be seen as is xanthochromia in some patients
c.Rare hypoglycorrhachia with sugars below 40mg/dL
d.Moderate increase of protein
2.PCR is positive in the serum and the CSF
a.MRI
i.Classic medial and inferior temporal lobe hemorrhagic lesions
1.Syphilis has reemerged worldwide in the late 1990s
2.Patients with concurrent HIV may comprise from 1/3 to 2/3 of new patients in some populations
3.Syphilis may increase viral loads in HIV patients with concomitant decrease of CD4 cell counts
4.Patients with HIV have an increased risk of developing neurologic complications
1.The treponeme most often invades the CNS within 3 to 18 months after infection
2.The initial occurrence that causes neurosyphilis is meningitis which occurs in approximately 25% of all patients
3.Clinical syndromes include:
a.Syphilitic meningitis
b.Meningovascular syphilis
c.General paresis
d.Tabes dorsalis
e.Optic atrophy
f.Meningomyelitis
4.There is usually a combination of two or more syndromes with one predominant
1.Tabes dorsalis usually develops 15 to 20 years after the initial infection
2.The major symptoms are lightening pains, ataxia and urinary incontinence
3.Neurologic examination reveals:
a.Impaired or absent vibratory and position sense in the lower extremities
b.Positive Romberg sign
c.Absent knee and ankle muscle stretch reflexes
d.Sensory ataxia
e.Minimal or no motor weakness
f.Lightening pains:
i.Occur in more than 90% of patients
ii.They are sharp and lancinating, more frequent in the legs but can occur from the face to the feet
iii.Rarely they are persistent in one location
iv.Associated paresthesias include that of coldness, numbness and tingling
v.The lancinating pain and paresthesias are intermittent and may last for hours or days
vi.There is loss of thermal, pain and tactile modalities in affected areas
vii.Often associated neurological complications include:
1.An insensitive and hypotonic bladder that causes overflow incontinence
2.Impotence
3.Constipation and megacolon
4.A staggering stamping gait
5.Trophic foot ulcers and Charcot joints are characteristic; Charcot joints occur in approximately 10% of tabetic patients and affect the hip and knee joints most frequently
viii.Rarely seen is gastric crisis:
1.The patient suddenly experiences epigastric pain that spreads around the body or up over the chest
2.Patients may sense a feeling of thoracic constriction that is associated with nausea and vomiting; symptoms may last for days; attacks end abruptly
3.Patients have residual soreness of the epigastric skin
4.Other paroxysmal pain attacks that occur with tabes dorsalis include:
a.Intestinal crisis with colicky abdominal pain and diarrhea
b.Laryngeal pain
c.Laryngeal pain with associated:
i.Gulping movements
ii.Dyspnea
d.Rectal pain with associated:
i.Tenesmus
e.Bladder crisis with dysuria
1.Atrophy of the posterior roots most prominently of the lumbosacral roots
2.Degeneration of the dorsal columns
3.Loss of neurons in the DRG
4.Normal peripheral nerves
5.The major mechanism appears to be inflammation along the posterior roots
1.The CSF:
a.Mild pleocytosis (lymphocytic)
b.Minimal to moderate protein elevation with positive IgG oligoclonal bands
c.Normal glucose
d.In long standing patients, the spinal fluid can be normal
2.The standard serum evaluations:
a.VDRL
b.FTA-ABS
c.Rapid plasma reagin (RPR)
d.Treponema pallidum particle agglutination assay (TPPA)
3.47-PCR and polA-PCR for CSF analysis