Neuromuscular disease (including some myelopathies) Flashcards

Question

ALS pathology

Answer 1

Insoluble proteins in the cytoplasm of degenerating neurons: TAR DNA-binding protein (TDP-43) is major component of neuronal cytoplasmic inclusion and colocalizes with ubiquitin Ubiquilin 2 colocalizes with pathologic inclusions as well

Answer 2

Poliovrus Coxsackie A & B _West Nile Virus:_ **_flavivirus_**_, can also cause meningoencephalitis and a GBS-like neuropathy that may be axonal or demyelinating_ Enterovirus Echovirus

Answer 3

AR, linked to chromosome 51, 2nd MC AR disorder Has 4 types that are defined clinically but the phenotype predicts the genotype

Answer 4

AR, linked to chromosome 51, 2nd MC AR disorder Has 4 types that are defined clinically but the phenotype predicts the genotype

Answer 5

Werdnig-Hoffmann – Onset usually by 3 months, always by 6 months – Alert face and normal eye movements – Death: 50% by 7 months, 95% by 17 months SMA type 1, infantile SMA or Werdnig–Hoffman disease presents with decreased fetal movements, neonatal hypotonia, and weak cry. Patients with SMA type 1 exhibit head lag and frog-leg posture when supine, and are never able to sit up or achieve antigravity strength in the arms or legs. Diffuse areflexia is often present. Bulbar involvement leads to dysphagia, and respiratory involvement occurs. Death usually occurs by 2 years of age. Gene-therapy for SMA: Zolgensma is indicated for the treatment of children less than two years of age with SMA. The product is an adeno-associated virus vector-based gene therapy that targets the cause of SMA. The vector delivers a fully functional copy of human SMN gene into the target motor neuron cells. A one-time intravenous administration of Zolgensma results in expression of the SMN protein in a child’s motor neurons, which improves muscle movement and function, and survival of a child with SMA.

Answer 6

Dubowitz diseas – Onset \< 18 months, never stand independently In SMA type 2, intermediate SMA, symptoms begin in the first 1 to 2 years of life, with motor delay and tremor in some cases. This form is less severe than SMA1, with most children being able to sit unsupported, but significant contractures develop, and most are not able to ambulate.

Answer 7

Kugelberg-Welander – Onset \> 18 months, may walk SMA type 3, juvenile SMA or Kugelberg–Welander disease, typically presents in childhood (between ages 5 and 15 years) with difficult walking. The clinical picture is one of proximal muscle weakness, a fine action tremor, and fasciculations. Patients often remain ambulatory into adulthood.

Answer 8

Adult onset SMA type 4, adult-onset SMA or pseudomyopathic SMA, is the least common and least severe. Symptoms typically begin in the third to fourth decade of life, and include proximal muscle weakness, with the quadriceps being prominently involved, and fasciculations. Ambulation into late adulthood is common. Cranial nerve and respiratory involvement is rare.

Answer 9

Telomeric SMN1 is mutated in 95% of SMA SMN1 and SMN2 genes nearly identical but splicing causes production of different SMN protein, SMN2 skips exon 7 _Copy # of SMN2 gene inversely related to severity of disease_ _Absence of SMN1 and SMN2 is lethal_ Total amount of full length SMN protein is probably the best predictor of disease severity

Answer 10

Kennedy's disease Bulbospinal muscular atrophy Male sex (1:50,000) Cramps Elevated CPK (\<1000) Facial myokymia Gynecomastia Impotence, infertility, testicular atrophy NCS: reduced sural amplitudes EMG: chronic denervation

Answer 11

``` Trinucleotide repeat (CAG) in androgen receptor gene Actually X-linked dominant with reduced penetrance in females because of lower testosterone levels Toxic gain of function of abnormal receptor causes hormone dependent neurodegeneration _– Androgen antagonist therapy has so far failed in clinical trials_ ```

Answer 12

Inflammatory - Guillain-Barré syndrome (GBS) – Idiopathic/Postinfectious – Parainfectious: HIV, HBV, EBV, CMV, Lyme, toxoplasmosis – Associated with lymphoma Toxic – Diphtheria – Buckthorn berry intoxication

Answer 13

_Acute demyelinating_ GPR that produces an _exotoxin-\>neuropathy, cardiomyopathy_ Acute illness: nasopharyngitis, tonsillitis, laryngitis _Biphasic neuropathy_ _- Acute: local effects of toxin, palatal, and pharyngeal sensory loss with dysphonia and dysphagia_ _-8-12 weeks after infection: radiculoneuropathy that clinically resembles GBS_ _-Cardiac involvement 2/2 dysautonomia or myocarditis_ _\*Antitoxin dec severity of neuropathy if given early_

Answer 14

Acute demyelinating May be preceded by minor infection: campylobacter jejuni, mycoplasma pneumoniae, Zika virus May be preceded by vaccination or surgery CSF shows Albumino-cytologic dissociation Autonomic dysfunction Common electrodiagnostic pattern: loss of median sensory with present sural sensory Non-length-related • IVIG, plasmapheresis equally effective, no role for steroids

Answer 15

Inflammatory: CIDP Toxic: Long-list Hereditary: CMT, HNPP, CMTX, Refsum, hereditary leukoencephalopathies

Answer 16

Chronic demyelinating S(x)s persisting beyond 8 weeks Associated with paraproteinemia – Monoclonalgammopathyof undetermined significance – Waldenström’s macroglobulinemia IgMκ – Osteosclerotic myeloma IgGλ or IgAλ Associated with lupus, melanoma, HIV

Answer 17

_Chronic demyelinating_ Male \> female _Often presents with distal arm weakness in the distribution of a named nerve_ _Important differential diagnosis for ALS_ _Hallmark of diagnosis is conduction block in a motor nerve with normal sensory conduction through that segment_ _IgM directed against GM1 antibodies in 20-80%: these may also be found in patients with Acute Motor Axonal Neuropathy (AMAN)_ • IVIG is first line therapy Alo known as multifocal motor neuropathy with conduction block. This condition is a purely motor demyelinating neuropathy that presents with asymmetric weakness from involvement of individual peripheral nerves, hypo- or areflexia in the distribution of affected nerves, and no sensory manifestations. _CSF studies show normal protein levels, in contrast to acute and chronic demyelinating polyneuropathies_. _Anti-GM1_ antibodies have been detected in this condition, but the presence of these antibodies is not required to make the diagnosis, and _does not predict response to therapy_. Electrophysiologic testing demonstrates typical conduction block in various nerve distributions. The presence of conduction block is not, however, required to make the diagnosis if there are other features of demyelination, and response to treatment is not different between patients with or without conduction block. Sensory NCS are normal. _Patients with MMN do not have a good response to steroids or plasmapheresis, and some may worsen with these therapies. The use of intravenous immunoglobulin has been shown to be of benefit and is associated with clinical improvement. Other therapies that have been reported to be beneficial are rituximab and cyclophosphamide._

Answer 18

Diphtheria (acute) Buckthorn berry (acute) Amiodarone Hexachlorophene Perhexilene N-Hexane (glue sniffing) Chloroquine Procainamide FK-50

Answer 19

Chronic/hereditary demyelinating 1A: AD, chromosome 17, PMP22 duplication where PMP is the intrinsic membrane protein of compact myelin 1B: AD, chromosome 1, MPZ mutation for myelin protein 0 gene

Answer 20

Chronic/hereditary demyelinating neuropathy Hereditary Neuropathy with Liability to Pressure Palsies: AD, chrom 17, PMP 22 deletion

Answer 21

Chronic/hereditary demyelinating X-linked, connexin 32 mutation, intermediate conduction velocities

Answer 22

Chronic/hereditary demyelinating _AR, peroxisomal disorder with elevated serum phytanic acid, retinitis pigmentosa, cardiac failure_ _– Treat with low phytanic acid diet_

Answer 23

Chronic/hereditary demyelinating neuropathy _Metachromatic leukodystrophy: AR, chrom 22, arylsulfatase A_ _Krabbe’s Disease: AR, chrom 14, galactocerebroside β-galactosidase_ Cockayne’s syndrome: AR, chrom 5, progeria-like syndrome

Answer 24

AMAN Porphyria Toxins Tick paralysis

Answer 25

Inflammatory and vascular: collagen vascular diseases, vasculitides, paraproteins, amyloidosis, cryoglobulins, sarcoidosis (with associated myopathy) Metabolic/systemic disorders: diabetes, impaired glucose tolerance, celiac disease renal and hepatic failure, primary biliary cirrhosis, critical illness, hypothyroidism (also see in COPD, HLD, porphyria) Nutritional - vitamin deficiencies: B12, E, Copper Inherited: CMT2, Giant axonal neuropathy, SCA, ataxia-telangiectasia Toxic - long list

Answer 26

Chronic axonal neuropathy: inflammatory and vascular– Small fiber neuropathy, often painful – Autonomic features prominent – Carpal tunnel syndrome – Cardiomyopathy, nephrotic syndrome – Amyloid is extracellular • connective tissue and vessel walls – Acquired • Paraprotein, often λ light chain • Multiple myeloma may be diagnosed later – Hereditary • AD, transthyretin mutation, chrom 18 • Liver transplant prevents progression

Answer 27

Chronic axonal neuropathy: inflammatory and vascular • Immunoglobulins that reversibly precipitate below body temperature (37°C) • May be essential or associated with: – Paraprotein +/- lymphoproliferative disease • Waldenström’s macroglobulinemia, multiple myeloma – Hepatitis C, HIV (RF often present) – Connective tissue disease (mixed cryoglobulinemia) • Can be multifocal mononeuropathy (pathology is vasculitis) or polyneuropathy

Answer 28

Chronic axonal neuropathy: metabolic, systemic • Gluten sensitive enteropathy: T-cellmediated immune response against ingested gluten • Peripheral neuropathy _• Ataxia due to Purkinje cell loss_ _• IgA directed against tissue trans glutaminase and gliadin_ • Intestinal biopsy is still gold standard – Blunted intestinal villi, hyperplastic crypts, inflammation • Treat with gluten-free diet

Answer 29

Chronic axonal neuropathy: nutritional B12 (Cobalamin): neuromyelopathy – Subacute combined degeneration – Loss of fibers in posterior columns and lateral tracts – Sensory\>motor neuropathy, optic neuropathy Other: dementia, megaloblastic anemia, glossitis _– If intermediate B12 (100-200), elevated methylmalonic acid → sucinyl co A in rxn with B12 and/or homocysteine →methionine confirm deficiency_ – Causes • dietary (vegetarians) • deficiency of intrinsic factor (required to absorb vitamin B12), secondary to post-gastrectomy syndrome, pernicious anemia (antibody to parietal cells) Serum methylmalonic acid and homocysteine levels should be obtained when following patients with B12 deficiency receiving treatment.

Answer 30

Chronic axonal neuropathy: nutritional E (α-tocopherol): large fiber sensory neuropathy with sensory ataxia – Loss of fibers in posterior columns and dorsal root – May occur in malabsorption syndromes (chronic bowel disease, cystic fibrosis) – Also in A-β-lipoproteinemia • Retinitis pigmentosa • Acanthocytosis • Treat with diet rich in medium chain triglycerides to replace fat

Answer 31

_Chronic axonal neuropathy: nutritional_ _Neuromyelopathy_ _– Often seen with high zinc levels, should stop zinc supplementation_

Answer 32

Chronic/hereditary _axonal_ neuropathy _AD_, less common than CMT1, diverse genetic causes Most common mutation: _MFN2 which encodes mitofusin 2, an intrinsic membrane protein in mitochondria_

Answer 33

Chronic axonal neuropathy: hereditary Childhood onset with gait disorder, _gigaxonin_ mutation

Answer 34

_Chronic axonal neuropathy: hereditary_ _AD, some with axonal polyneuropathy that is sensory or sensory-motor_

Answer 35

Chronic axonal neuropathy: hereditary AR, defect in DNA repair

Answer 36

GBS: seroconversion, +cells inCSF CIDP: also + cells in CSF Mononeuropathy: consider herpes zoster Mononeuritis multiplex/Polyradiculopathy – vasculitis, CMV, lymphoma Axonal polyneuropathy, sensory \> motor – Dysesthetic pain prominent ALS variant – Elevated CSF protein, improvement with AZT Toxic: nucleosides (ddC,ddI,d4T,3TC) – Dose-dependent, painful, sensory

Answer 37

Meningovascular syphilis: Stroke syndromes – Syphilitic endarteritis of the great vessels – 5-12 years after untreated infection General paresis: Neuropsychiatric symptoms – Direct infection of the meninges and cortex – 15-20 years after untreated infection Tabes dorsalis: Neuromyelopathy _– Posterior columns of spinal cord and dorsal roots_ _– 18-25 years after untreated infection_ _– Gait ataxia, lightning pains,_ Charcot’s joints – CSF not always abnormal Treatment: PenicillinG(IV)

Answer 38

_Mycobacterium leprae_: gram + acid fast rod Infects _cool areas_: chin, malar face, ear lobes, buttocks, knees, lower legs Tuberculoid: focal skin lesions – Anesthetic, hypopigmented, hairless, dry Lepromatous: more diffuse disease Borderline: between tuberculoid and lepromatous Treatment: depends on extent

Answer 39

_Ixodes tick transmits spirochete Borrelia_ Erythema chronica migrans (painless) Acute disseminated syndrome – Fever, arthralgias, myalgias, headache, fatigue Meningoradiculitis may occur – often painful – GBS-like acute neuropathy Focal neuropathies (facial, plexopathies) Chronic sensory-motor axonal polyneuropathy

Answer 40

**Miller-Fisher variant: ophthalmoplegia, ataxia, and areflexa; associated with anti-GQ1B antibodies** _Facial diplegia with acral paresthesias: isolated LMN pattern facial weakness accompanied by paresthesias in the distal extremities and decreased or absent reflexes but without extremity weakness_ _Pharyngeal-cervical-brachial variant: dysphagia, neck weakness, proximal upper extremity weakness, and areflexia that is often limited to the upper extremities, and may also cause ptosis;_ **_anti-GT1a antibodies_** _may be seen with this variant_ **AMAN - acute motor axonal neuropathy - and AMSAN - acute motor and sensory axonal neuropathy - are axonal variants** ## Footnote **GM1, GM1b, GD1a, (and GalNac-GD1a for AMSAN)**

Answer 41

MADSAM - multifocal acquired demyelinating sensory and motor neuropathy: CIDP with sensorimotor asymmetric onset DADS - distal acquired demyelinating symmetric neuropathy (associated with anti-MAG IgM), responds poorly to immunotherapy: CIDP but distally predominant MMN - multifocal motor neuropathy: CIDP with asymmetric motor onset (GM1) CISP - chronic immune sensory polyneuropathy: CIDP but sensory predominant

Answer 42

Can have normal NCS/EMG Metabolic: diabetes Toxic: alcohol Infectious: HIV, HCV Inherited: Fabry's disease, hereditary sensory and autonomic neuropathy, amyloidosis Inflammatory: Sjogren's syndrome, sarcoid, celiac, paraneoplastic: _MC anti-Hu_

Answer 43

Pre-synaptic disease Pathophysiology: Auto-antibodies against pre-synaptic voltage-gated Ca2+ channels on cholinergic neurons _Clinical s(x)s: proximal weakness, mild ptosis but bulbar s(x)s rare compared to MG, autonomic sxs: dry mouth (77%); some with constipation, blurred vision, and erectile dysfunction; reflexes and strength may increase briefly immediately after exercise_ _D(x): VGCC antibodies present in 90% in LEMS but low titer positive in up to 24% patients with cancer without LEMS, 23% of ALS patients and 3% in MG -\> thus, VGCC antibody test is confirmatory only in those with the clinical and electrophysiologic features of LEMS; typical electrophysiology features on nerve conduction studies approach 100% sensitivity_

Answer 44

Pre-synaptic disease About half have underlying malignancy: m_ostly SCLC – 85% in one series, 2/3 of men and 1/3 of women with malignancy_ _– The remainder have autoimmune LEMS without cancer_ Warrants repeat malignancy screening – CT C/A/P, mammogram, colonoscopy, prostate or GYN exam _– PET in smokers over age 50_ _– if not present at the diagnosis of LES, most tumors become evident within the first two years after onset of LEMS, nearly always w/in 4 years of LES onset_

Answer 45

Pre-synaptic disease Food borne (due to ingestion of the toxin of the Clostridium botulinum bacterium) Wound botulism, usually in IV drug abusers (bacterium in the wound produces the toxin) Infant botulism (due to ingestion of the bacterium spores that germinate in the infant GI tract) _- unlike the adult forms, C. botulinum can be cultured from the stool of infants with botulism_

Answer 46

Presynaptic disease Toxin is spread via the vascular system and binds to a specific receptor (synaptotagmin II) on the pre-synaptic side of peripheral cholinergic synapses at ganglia and neuromuscular junctions After gaining entrance to the pre-synaptic cytoplasm, botulinum toxin binds irreversibly to intracellular SNARE proteins involved in acetylcholine (ACh) release\* Toxins A to G – A, B, E cause human disease – Cleave SNARE proteins used in the docking and fusion of the ACh vesicles with the pre- synaptic membrane, preventing transmitter release _– Toxins A and E cleave SNAP-25 (synaptosomal-associated protein-25), type C cleavers syntaxin and toxin B cleaves synaptobrevin/vesicle-associated membrane protein (VAMP)_

Answer 47

_Pre-synaptic disease_ _– some with infantile onset have genetic abnormalities in ACh packaging, re-synthesis or mobilization -\> produces paucity of ACh vesicles or reduced quantal release_ _– should be considered if: a positive family history, a lack of responsiveness to acetylcholinesterase inhibitors, absence of AChR antibodies or a slow progressive course dating back to childhood_

Answer 48

_Presynaptic disease_ _– competes with Ca2+ and interferes with ACh release_ _– often in patients with renal insufficiency who receive oral magnesium (e.g., laxatives) or during treatment for eclampsia_ _– ocular muscles spared_

Answer 49

Pre-synaptic disease _– Toxin (not identified) blocks pre-synaptic sodium ion influx – prevents pre-synaptic terminal depolarization (i.e., no Ca2+ influx and no transmitter release)_ – Ascending flaccid paralysis 3 to 7 days after tick attaches – diagnosis and treatment by finding and removing the tick – Rocky Mountain wood tick, Lone Star tick, American dog tick, Gulf coast tick

Answer 50

Post-synaptic disease Patients present with complaints of specific muscle weakness and not generalized fatigue Symptoms are best in the AM upon awakening; worsen late in the day, after exercise and in the heat About 10% have underlying thymoma Symptoms at onset:  ~50% Ocular only: present with ocular manifestations (ptosis and/or diplopia) - most develop ocular symptoms at some point -\> up to 50% of these remain ocular only, ocular MG, of other 50% that progress to general, 75% by 1 year of symptoms, 85-90% by 2-3 years  35% Mix of ocular, bulbar, neck and/or limb weakness  15% Bulbar only  Uncommon - isolated neck weakness or isolated respiratory only From Ching-Ching: Ocular muscles are most commonly involved, with ptosis and diplopia as the presenting symptom in 70% to 90% of cases. Up to 80% of such patients generalize to involve bulbar, limb, neck, and/or respiratory muscles within 2 years. In a minority (10% to 15%), involvement remains restricted to the eyes, so-called ocular myasthenia.

Answer 51

Post-synaptic disease Generalized myasthenia gravis – Auto-antibodies to ACh receptor (AChR) in most (80-85%) – One third to 1⁄2 of those MG patients without AChR antibodies have antibodies instead to muscle specific receptor kinase (MuSK) –The remaining ~10%, without demonstrable serum antibodies are termed “seronegative” (Maybe outdated) Ocular MG – ~50% have positive AChR antibody titers – None have MuSK titers – So, ~50% of OMG are seronegative

Answer 52

Post-synaptic – endplate acetylcholinesterase deficiency (produces depolarizing block!) – genetic defects of the AChR slow channel syndrome receptor deficiency  deficiency of associated proteins (rapsin or plectin)

Answer 53

Post-synaptic disorder _Exert their NMJ toxicity by the irreversible inhibition of acetylcholine cholinesterase (AChE)_ – produces excess ACh at the NMJ – excessively depolarizes the postsynaptic membrane – this impairs activation through persistent depolarizing block – produces weakness as well as autonomic and central nervous system dysfunction (altered sensorium often key – not seen in other NMJ disorders)\* Overdose or ingestion of certain pesticides Agents of war – inhibit the hydrolysis of Ach by AChE by binding to and phosphorylating the active sites of AChE  V – series (V = venomous) more potent – e.g., VX (venom X)  G – series (G = German) – e.g., GB (sarin)

Answer 54

– In patients with MG or LEMS may have excessive effect – Historical: curare (d-tubocurarine) occupies the same position on the receptor as ACh with an equal or greater affinity - a competitive antagonist – Used in anesthesia, such as vecuronium, atracurium, pancuronium

Answer 55

_Produces autoimmune MG with ACh receptor antibodies_ _Slowly resolves after discontinuation of the med_

Answer 56

_RNS at 2-3 Hz x6-10 times_ Normal muscles: No change in CMAP amplitude with repetitive nerve stimulation Myasthenia gravis or pre-synaptic disorders – Progressive decline in CMAP amplitudes with the first 4 to 5 stimuli. – Positive RNS test features  Decrement in CMAP amplitude _– Size: More than 10% in reduction in CMAP amplitude_  Measure from 1st to 3rd, 4th or 5th potential in train (whichever is smallest) [] Also see post-exercise (tetanic) potentiation and exhaustion Also see decremental response at low frequency RNS in pre-synaptic disorders

Answer 57

Sensitivity of RNS for MG is reduced when only distal muscles are tested (~ 50% recording from the hand to 90% with addition of recording from the trapezius, biceps, or face) MuSK-positive patients - higher yield with facial nerve RNS Important: If median or ulnar studies are normal, do proximal nerve (e.g., spinal accessory) and facial nerve RNS is only + in 15-45% of patients with ocular MG

Answer 58

Incremental responses (\>100%) – With high frequency RNS 30-50 Hz, or – Immediately after 10-20 seconds of maximal exercise  These features (low resting CMAP amplitudes and incremental responses after exercise) are not present in myasthenia gravis or other post- synaptic NMJ disorders Why? – Due to transiently increased concentration of calcium in the pre-synaptic terminal – This increases the number of ACh quanta released with each pre-synaptic action potential – This also underlies the brief clinical facilitation of reflexes and strength after brief exercise in LES

Answer 59

RNS Studies: summary\*  When a decremental response is present at 2-3 Hz RNS – Correlate with the needle EMG exam – CMAP amplitude at rest and immediately after exercise  Postsynaptic NMJ disorder, such as MG – Needle EMG shows no signs of active denervation – No increment in the CMAP after exercise  Presynaptic NMJ disorder, such as LEMS – Needle EMG shows no signs of active denervation – Increment \>100% in the CMAP after exercise

Answer 60

Simultaneously records potentials of two muscle fibers innervated by an individual axon – Measures this variability = "Jitter" – SFEMG is the most sensitive test for MG and LEMS  NB: AChR or MuSK antibodies are most specific test for MG – Abnormal jitter is not specific for MG May occur in other neuromuscular disorders, including ALS, polymyositis or LEMS

Answer 61

_The sensitivity of serum AchR binding antibodies is highest for generalized myasthenia, detecting antibodies in 70% to 95% of patients and lower for patients with ocular myasthenia_. Patients who are initially seronegative for binding, blocking, or modulating antibodies may seroconvert later in the course of their disease. In a minority of patients with autoimmune myasthenia in whom the binding antibody is not detectable, modulating or blocking antibodies may be present. In approximately half of all patients who are seronegative for antibodies against the acetylcholine receptor, anti–muscle-specific tyrosine kinase antibodies are present

Answer 62

Myasthenia gravis:  Symptomatic treatment – pyridostigmine (Mestinon®)  Immunotherapies – prednisone – azathioprine, mycophenolate mofetil, cyclosporine/tacrolimus  Rapid therapies – Plasma exchange – IVIG  Thymectomy Other cholinesterase inhibitors Oral: Neostigmine bromide (Prostigmin®) - 1⁄4 dose of pyridostigmine Parenteral: Pyridostigmine bromide - 1/30-1/60th the oral; (1-2 mg), Neostigmine methylsulfate: rarely used, 0.5 mg, Edrophonium (Tensilon®) - short-acting

Answer 63

Advantages – Few serious side effects Disadvantages – Effective minimally in many patients – Bothersome cholinergic side effects Cholinergic side-effects – Muscarinic: salivation, stomach cramps, diarrhea – Nicotinic: faciculations, muscle cramps Treatment of side-effects – Imodium, Lomotil – Robinul (glycopyrrolate), atropine

Answer 64

In patients with thymoma:  Indicated in all with thymoma – Important: Chest CT scan, or MRI, mandatory in all patients diagnosed with myasthenia (~10% have underlying thymoma)\* In patients without thymoma:  No randomized, prospective controlled studies – One currently in process  Probably beneficial in most – Under age 60 with generalized disease  Thought to have a slow onset of action – Generally 2 years or longer

Answer 65

Botulism Supportive care: Ventilatory support Antibiotics for C. botulinum bacterium  Not for food bourne – toxin ingested, not bacterium  Not for infant botulism – may cause lysis of the bacterium and dump toxin into gut increasing absorption  Used for wound botulism Equine serum heptavalent (A-G) botulism antitoxin for adult botulism (food-borne or wound)  Best if used w/in 24 hours – from the CDC only via State Health Departments (also, poison control centers); Reduces mortality, even if given later in the course  20% serum sickness and 3% anaphylaxis (since derived from horse serum) Human derived botulism antitoxin for IV use in infants less than 1 year of age (babyBIG)  Sooner the better; w/in 3 days of hospitalization best

Answer 66

Symptomatic therapy – 3,4 DAP is considered first line therapy 3,4-diaminopyridine (3,4-DAP) - prolongs depolarization of the pre-synaptic membrane after a nerve impulse, increases influx of calcium, and increases acetylcholine receptor release – Blocks pre-synaptic voltage-dependent potassium channels – Not yet approved in US (can get for compassionate use) – May cause seizures at high doses or in patients with seizure disorders Pyridostigmine (Mestinon®) – marginally effective, best when used with 3,4-DAP Immunotherapies Same approach as with myasthenia Prednisone Rapid therapies: IVIG and plasma exchange Chronic immunotherapies: Azathiopine, mycophenolate mofetil, cyclosporine/tacrolimus

Answer 67

Effective in MG, LEMS, CIDP, GBS, Isaac’s syndrome Used in certain paraprotein-associated neuropathies, Stiff-man syndrome, with questionable efficacy _Not effective in multifocal motor neuropathy (MMN) or inflammatory myopathies (polymyositis, dermatomyositis)_ _Works presumably by removing auto-antibodies and cytokines_ _Reduces immunoglobulin levels rapidly but these rebound within weeks if no concurrent immunosuppression_ Considerations: _5 exchanges over 10-14 days for most_ _More effective if done every other day than daily_ Reduces immunoglobulin levels rapidly but these rebound within weeks if no concurrent immunosuppression _Short onset of action (3-10 days)_ Adverse effects: hemodynamic disturbances, infections, sepsis and other line complications

Answer 68

Controlled trials show effective in MG, LEMS, GBS, CIDP, MMN In some patients with inflammatory myopathies (PM, DM); IgM associated neuropathy; stiff-man syndrome Not effective in IBM; most patients with paraprotein-associated neuropathy Multiple mechanisms: competition with autoantibodies (anti-idiotype effect), inhibits cytokines, inhibits complement deposition, blocks Fc receptors on macrophages and immunoglobulins on B cells Considerations – Usual initial dose is 2 g/kg over 2-5 divided daily doses – Maintenance dose is generally 1-2 g/kg every 3-6 weeks, depending on the clinical response Adverse effects – Common: headache, chills, flu-like sxs, fluid overload – Less common: rash, aseptic meningitis – Serious: acute renal tubular necrosis (usually reversible), thromboembolic events (DVT, PE, MI, stoke), anaphylactic reactions (in those with IgA deficiency)

Answer 69

Quicker acting, shorter term use – Corticosteroids Slower acting, long-term use – Azathioprine (Imuran®) – Cyclosporine and tacrolimus – Mycophenolate mofetil (CellCept®) – methotrexate Less commonly used – Cyclophosphamide – Rituximab

Answer 70

Prednisone: most commonly used drug Advantages: short onset of action (0.5 to 2 months), can be used during pregnancy, inexpensive Adverse effects: numerous Data supports effectiveness in some inflammatory myopathies (PM and DM), MG, CIDP Not effective in GBS, MMN, and most paraprotein- associated neuropathies _High-dose daily (1 mg/kg) use is best in most; every other day dosing is often not adequate for initial clinical respons_e  Important exception is MG ! (unless concomitantly treated with IVIG or plasmapheresis) – Transient paradoxical worsening occurs 5 to 10 days after the initiation of high-dose corticosteroids – serious in 50% and respiratory failure in up to 10%  This transient worsening is prevented by the quick onset of action of the rapid therapies

Answer 71

Purine analogue that suppresses the activation of Rac1 target genes (interferes with T- and B-cell proliferation) – primarily T cell apoptosis - Used most often in MG; only demonstrated effective in MG +/- inflammatory myopathies - Doses 1.5-2.5 mg/kg daily Pretreatment – suggest checking TMPT (thiopurine methytransferase) enzyme levels in serum-\> if homozygous negative for TMPT (1 in 300) should not receive drug – develop severe bone marrow toxicity Onset of action is slow – \> 8 months: may not achieve peak effectiveness for 1.5 to 2 years Side-effects: Anemia/leukopenia\* – dose related Liver function abnormalities\* (should not use with allopurinol that may greatly worsen this effect) Flu-like reaction in 10 to 20 % Small increased risk of non-Hodgkins lymphoma and non-melanotic skin cancer – not yet demonstrated in neurologic use _\*follow CBC and LFTs monthly x 6, every other month x 6, and then quarterly_

Answer 72

_Inhibits predominantly T-lymphocyte-dependent immune responses_ – Reduced synthesis of NFAT and IL-2 – Same mechanism as tacrolimus Shorter onset than azathioprine (1-3 months) Effective in MG; some benefit in CIDP and DM Doses 2 to 2.5 mg/kg BID – aim for low theraleutic level for chronic renal transplant or lower Serious side-effects Nephrotoxicity\* – uncommon with neurologic doses (5 mg/kg qd in two divided doses) and monitoring of trough drug levels and renal function studies Hypertension\* – treat aggressively; potentiates the nephrotoxicity Interacts with many other drugs\* Especially avoid NSAIDs and nephrotoxic drugs \*monitor renal function, BP, trough levels

Answer 73

_Selectively blocks purine synthesis in lymphocytes_ - inhibits their proliferation Favorable experience in case series in MG, CIDP, PM RCTs in MG do not show superiority of MMF and prednisone over prednisone alone – but the studies performed are limited by short period of treatment (3 and 9 months, respectively) Well tolerated with few side effects Side effects – anemia, possible low risk for late malignancies

Answer 74

Antagonist of folate metabolism Most commonly used in inflammatory myopathies (PM and DM); may be helpful in some patients with CIDP and MG (but experience is limited outside of PM and DM) Acts faster than azathioprine Dosing is often 2.5 mg every 12 hours times 3 per week (total weekly dose 7.5 mg); increased as needed by 2.5 mg per week to max of 25 mg per week in 3 divided doses given 12 hours apart Adverse effects: Pneumonitis (more common with IV dosing), stomatitis, GI symptoms, leukopenia, hepatotoxcity – hepatic fibrosis may not be heralded by LFT abnormalities; with chronic use may need liver biopsy for monitoring

Answer 75

Muscular dystrophy Most common form of MD Dystrophin encoded on X-chromosome _– Large protein with high spontaneous mutation rate (1:10,000) found in skeletal and cardiac muscle_ Mutations cause: _– Duchenne MD: \<3% normal dystrophin_ _– Becker MD: reduced quantity of abnormal dystrophin – Dilated cardiomyopathy +/- muscle involvement_ – Milder phenotypes: exercise-induced cramps/myalgias – Manifesting females: CPK, cardiomyopathy

Answer 76

Muscular dystrophy X-linked 1:3300 live male births 30% new mutations • Frameshift mutations This patient has Duchenne muscular dystrophy. This condition is a dystrophinopathy, inherited in an X-linked recessive fashion, and is the most common genetic muscle disease, affecting 1 in 3,500 live male births. About a third of the cases are caused by spontaneous mutations in the dystrophin gene, so there may not be a positive family history.

Answer 77

Muscular dystrophy Delayed motor milestones Proximal weakness Lordotic, waddling gait Gower’s sign Hypertrophy of calves, gluteals, lateral vasti, deltoid, infraspinatus Loss of ambulation in preteen years (~11) CPK elevated from birth Progressive contractures Non-progressive mental retardation frequent Cardiomyopathy: sinus tach early, heart failure late concomitant with respiratory failure with pulmonary hypertension Scoliosis, onset with loss of ambulation This condition presents early in life and manifests with weakness and delayed development of motor milestones. These children have frequent falls, and difficulty walking, running, and rising from supine and sitting positions. Weakness is significant in the proximal muscles, predominantly in the iliopsoas, quadriceps, and gluteals, as well as the shoulder girdle and upper limbs. It also tends to affect the pretibial muscles. These patients have pseudohypertrophy of the calves due to fibrosis. They also have scapular winging and contractures. Ocular, facial, and bulbar muscles are usually spared. Cardiac involvement includes arrhythmias, cardiomyopathy, and heart failure. It is recommended that all patients with Duchenne muscular dystrophy undergo cardiac evaluation, even if asymptomatic from a cardiac standpoint. Mild developmental delay with a subnormal intelligence quotient (IQ) may be seen. These children become wheelchair or bed-bound, and may eventually die of respiratory failure and pulmonary infections. Creatine kinase values range from 10 to 100 times higher than normal. Needle EMG shows fibrillations, positive waves, and myopathic motor unit potentials. Muscle biopsy show endomysial fibrosis, loss of muscle fibers with residual fibers of different sizes, some of which are very large and eosinophilic, and others very small and atrophic. Degeneration and regeneration, as well as necrosis and macrophage invasion, may also be seen. he diagnosis of Duchenne muscular dystrophy is made by genetic testing of the dystrophin gene or by absent dystrophin immunostaining on muscle biopsy.

Answer 78

Muscular dystrophy

Answer 79

Muscular dystrophy Corticosteroid treatment prolongs ambulation – This is based on non-randomised data but has become standard of care Antisense oligonucleotide-induced exon skipping – converts a Duchenne phenotype to a Becker phenotype – Largest trial on a drug that skips exon 51 – (13% of DMD patients)

Answer 80

Muscular dystrophy Most mutations are in-frame deletions Variable clinical severity • Clinical onset usually \> age 7 • Low-Average IQ • Cardiac involvement may predominate, degree is not predicted by muscle weakness – Obligate female carriers should be screened for cardiomyopathy However, patients with Becker’s muscular dystrophy present later in life, sometimes in childhood, but more frequently in adolescence or adulthood. Given the milder phenotype, _these patients are able to ambulate beyond the second decade of life, cardiac involvement occurs but is less frequent, and intelligence quotient (IQ) is usually normal_. Needle EMG shows fibrillations, positive waves, and polyphasic short motor unit potentials. The biopsy will detect similar findings as in Duchenne muscular dystrophy (see questions 19 and 20); however, dystrophin is not absent in Becker’s muscular dystrophy, but structurally abnormal or present in a smaller than normal amount.

Answer 81

Muscular dystrophy Autosomal dominant, trinucleotide CTG repeat (chrom 19,myotonic dystrophy protein kinase gen aka DMPK gene) – Probably due to aberrant regulation of alternative RNA splicing Present early in adult life: Ptosis with facial weakness, Early limb weakness is mild and distal vs DM2 which is proximal, Myotonia: slow relaxation of voluntary muscle contraction, abates with continued activity Other features: Cognitive changes: apathy, inertia, Central hypersomnolence Cataracts: multicolored subcapsular opacities Cardiac conduction defects – Must avoid pro-arrhythmic meds for myotonia (quinine, procainamide, +/- dilantin); choose mexiletine if treatment absolutely necessary Gonadal failure: testicular atrophy Pregnancy complications _Frontal baldness, atrophy of the masseters and temporalis_

Answer 82

Creatine kinase levels may be slightly elevated. EMG demonstrates myotonic discharges and short, sharp, early recruiting motor unit potentials with fibrillations. Histopathologically, muscle biopsy demonstrates marked central nucleation, type 1 fiber atrophy, peripherally placed sarcoplasmic masses, ring fibers, and pyknotic nuclear clumps.

Answer 83

Muscular dystrophy _Anesthesia Considerations_ _– Induction with depolarizing relaxants (succinylcholine) and reversal (neostigmine) may worsen myotonia (no clear increase in malignant hyperthermia)_ _Apnea risks_ _– Benzodiazepines, barbiturates, opiates_

Answer 84

Muscular dystrophy Early childhood version of myotonic dystrophy

Answer 85

Muscular dystrophy Autosomal dominant CCTG expansion (_chrom 3, ZNF9 - an intron of the zinc finger protein 9 gene on chromosome 3q, and it is associated with intranuclear accumulation of the expanded RNA transcripts)_ Weakness is proximal Face is usually spared Clinical myotonia may be absent Cataracts Cardiac conduction defects It is autosomal dominant and is characterized by myotonia and proximal muscle weakness (as opposed to the distal weakness characteristic of DM1, discussed in question 12). Cataracts and cardiac involvement also occur less commonly in DM2 compared to DM1. Histopathologic findings include muscle fiber size variability, many fibers with multiple (5 to 10 or more) internalized nuclei, and atrophic fibers with nuclear clumps.

Answer 86

Muscular dystrophy **Early contractures of biceps, gastrocnemii: flexes the knee (and foot), posterior cervical muscles (elbows, ankles, and neck)** Slowly progressive weakness starts humeroperoneal Cardiomyopathy: conduction defects leading to complete heart block and atrial paralysis – Pacemaker, defibrillator, anticoagulation, transplant • EMD1: X-linked - mutation in gene encoding protein emerin: nuclear membrane protein • EMD2: AD (rarely AR) - mutation in gene encoding _lamins_ A and C: nuclear membrane proteins – Cardiac abnormalities prominent – Relatively mild limb-girdle weakness – Contractures less prominent – Allelic with LGMD1B (chrom 1) Muscle weakness tends to affect the upper arms and shoulder girdle muscles first and later the pelvic girdle and distal leg muscles. There is no pseudohypertrophy of the calves, and intelligence quotient (IQ) is normal. Cardiac involvement is prominent, with serious conduction abnormalities, often requiring pacemaker placement.

Answer 87

Autosomal dominant fashion and is caused by deletions in a 3.3 kb repeating sequences, termed D4Z4, located on chromosome 4q35.

Answer 88

Muscular dystrophy _Face – transverse smile, no straw/whistle, weak eye closure_ _Scapular fixators (latissmus, rhomboids, serratus anterior, lower trapezius), leads to upriding trapezius_ Pectoralis – reversal of crease Biceps \> triceps, deltoid spared _Tibialis anterior (foot drop)_ _Pelvic girdle with abdominal weakness and protuberance_ _Asymmetric, stepwise progression_ No convincing cardiac features _Sensorineural hearing loss for high tones_ _Asymptomatic retinal telangiectasias_ _Albuterol – increased muscle mass but no increase in strength_ _FSHD is slowly progressive, and predominantly affects the face and shoulders, though later in the course of the disease, the lower extremities are affected as well. These patients have weakness that can be asymmetric, and present with difficulty lifting their arms above their head, with prominent involvement of the upper arms (scapular muscles, biceps, triceps, trapezius, serratus anterior, and pectoralis), with_ **_relative sparing of the deltoids._ The upper arm seems to be more atrophic than the forearms, making the bones of the shoulder appear prominent. Weakness of the abdominal muscles produces the “Beevor sign,” in which the umbilicus moves upward with neck flexion.** **Cardiac involvement is rare and intelligence is typically normal. Creatine kinase levels are normal to slightly elevated.** Age of onset is on average 16 in males and 20 in females, but can be variable, ranging between the first and sixth decades of life.

Answer 89

Muscular dystrophy Autosomal dominant Late onset Chrom 14 Short expansion in the PABPN1 gene Muscle biopsy: rimmed cytoplasmic vacuoles (variation in fiber size, intranuclear tubular filaments) EM: tubulofilamentous nuclear inclusions that contain PABPN1 proteins Ptosis and dysphagia, later weakness of proximal, facial and extraocular muscl Autosomal dominant late-onset muscular dystrophy with manifestations restricted to the ocular and pharyngeal regions. It is more frequent in patients of French-Canadian descent, and is caused by a GCG (GCN where N can be A/T/G/C, MC G) repeat expansion in the poly-A–binding protein 2 gene on chromosome 14q11

Answer 90

Non-inflammatory Mild or no elevation of CPK _Skeletal muscle affected only_ _Distal muscles affected early_ Onset in teens or early adult life AR or AD _Rimmed vacuoles (not specific)_ Tubulofilamentous inclusions on EM (thicker than those in OPMD)

Answer 91

Inflammatory myopathy Proximal weakness: quadriceps, posterior neck Dysphagia common Cardiac: arrhythmia, dilated CM Pulmonary: interstitial lung disease, respiratory muscle weakness (restrictive deficit) _– Associated with Jo-1 antibody (an antisynthetase antibody)_ Overlap syndromes with collagen-vascular diseases (SLE, RA, Sjogren’s, MCTD) _Association with malignancy_ _Much higher in DM, age \> 40 and men_ _Cancer diagnosis highest in first 2 years_ _Carcinoma: ovary & stomach overrepresented_ _DM more common in children_ _Steroid responsive (and other immunosuppressants)_ _Drug induced by D-penicillamine (treats RA), same as MG_

Answer 92

Inflammatory myopathy An inflammatory infiltrate composed of lymphocytes and macrophages surrounding muscle fibers. There are regenerating and necrotic fibers. These findings are characteristic of polymyositis, and neither rimmed vacuoles nor _perifascicular atrophy_ is seen. _Perivascular infiltration, perimysial, endomysial_ inflammation

Answer 93

Inflammatory myopathy Also with perivascular inflammation, but no perimysial or endomysial inflammation Key is perifascular atrophy

Answer 94

Inflammatory myopathy _Most common inflammatory muscle disease after age 50, male \> female_ Finger flexors, quadriceps, biceps, triceps, iliopsoas, tibialis anterior Dysphagia in 30% CPK \< 1000 Treatment refractory

Answer 95

Inflammatory myopathy Endomysial inflammation (like polymyositis), groups of atrophic fibers, and i_ntracytoplasmic vacuoles with granular material known as rimmed vacuoles_, which are characteristic of inclusion body myositis.

Answer 96

Inflammatory myopathy HIV PM HIVI BM HIV necrotizing myopathy _HIV nemaline myopathy_ _AZT (zidovudine) myopathy – mitochondrial myopathy with ragged red fibers_

Answer 97

Structural change in the muscle fiber No degenerating and regenerating fibers vs dystrophies Early onset with hypotonia and weakness Genetic basis _Non-progressive_

Answer 98

Nemaline Myopathy _Muscle fibers contain rod-shaped structures_ Mild, moderate and severe forms AD, AR or sporadic _• Facial weakness sparing extraocular muscles_ _• Spares the heart_ _• May be a secondary finding (HIV myopathy)_

Answer 99

Mutation in ryanodine receptor (chrom 19, same as myotonic dystrophy) Associated with malignant hyperthermia AD most common, parent often clinically unaffected Ambulation usually achieved Skeletal deformities, cramps common Respiratory and cardiac involvement uncommon

Answer 100

``` In general prefer _non-depolarizing muscle relaxants_ _Avoid succinylcholine (depolarizing relaxant)_ _Avoid halothane, associated with malignant hyperthermia_ ```

Answer 101

Inc risk with enzyme (CYP34A) inhibitors: _cyclosporine, gemfibrozil, erythromycin, nicotinic acid, antifungals_ _May also be associated with increased risk of neuropathy_

Answer 102

Acute (critical illness myopathy): in combo with neuromuscular blocking agents (pancuronium), severe quadriplegia with respiratory involvement Chronic: unlikely with doses \< 10 mg daily, also seen in endogenous Cushing disease

Answer 103

Three types Thompsen - AD, in infancy, mild (painless) myotonia and hypertrophy but no weakness Becker's - AR, onset at 4-12 yo, more severe myotonia with associated weakness, muscle hypertrophy, "Herculean" phenotype Myotonia levior: AD, later onset, mild myotonia, no muscle hypertrophy Extreme muscle stiffness due to delay relaxation "Warm up", stiffness subsides with repeated muscle contraction Allelic in CLCN1, a muscle CL channel The main manifestation is myotonia, which is an impaired muscle relaxation as seen when the patients cannot relax their handgrip after grasping an object, and also manifested on percussion, leading to contraction and delayed relaxation. Myotonic potentials can be detected on EMG. Propofol and depolarizing neuromuscular blocking agents may aggravate the myotonia, and patients may have prolonged recovery. Mexiletine is the treatment of choice.

Answer 104

AD, Na channel mutations, allelic with the periodic paralyses Similar to MC, failure of relaxation after muscle contraction BUT Temperature sensitive stiffness, may experience periodic paralysis Provoked by cold No "warm up" phenomenon. In fact, myotonia worsens with repeated muscle action Typically more limited to forearm and facial muscles This patient has paramyotonia congenita, which is an autosomal dominant channelopathy caused by a mutation in the sodium channel gene SCN4A. The manifestations are similar to those of myotonia congenita; however, unlike in myotonia congenita, in paramyotonia congenita, there is no “warm-up” phenomenon. Rather, repeated exercise accentuates myotonia, which is most clearly appreciated in the eyelids. Hence the name is derived from “para”-doxical reaction to exercise. Exposure to cold worsens the myotonia and may precipitate weakness, also in contrast to myotonia congenita. Percussion myotonia is rare, but can be seen after exposure to cold. EMG after cold exposure can also demonstrate fibrillation potentials followed by electrical inexcitability.

Answer 105

AD, reduced penetrance, more common in males 3:1 Ca (type 1) and Na (type 2) channel mutations Onset at any age, typically second decade Can be provoked by low K, carbohydrate load (can trigger it via glucose load in clinical testing), alcohol, heavy exercise, cold, and emotional stressors Attacks typically begin in AM, proximal\>distal affect, respiratory muscles not affected, low serum K during attack, may have elevated CK Weakness persists for hours with mild residual weakness for days Type 1 is the dihydropiridine receptor (CACNA1S) Tx: avoid triggers; carbonic anhydrase inhibitors such as acetazolamide and potassium-sparing diuretics are also useful in treating this condition.

Answer 106

AD, highly penetrant Na channel mutation (like hypoK PP type 1 and paramyotonia congenita) - SCN4A Provoked by high K (provocative testing with administration of K), rest after heavy exercise, fasting (hot and cold temperatures) Onset commonly in infancy or childhood Attacks one on quick, milder, briefer than hypoK variety \<1 hr, serum K is typically normal Residual weakness not typical Treatment is focused on avoiding triggers. During attacks, glucose can be provided, and as prophylactic therapy, thiazide diuretics can be used.

Answer 107

Caused by chronic use of exogenous corticosteroids or by endogenous hypercortisolism,. Mild or moderate and proximal weakness. Needle EMG findings are non-specific and creatine kinase levels are usually normal. Histopathologically, there is atrophy of type II fibers. Management of this condition involves treatment of the underlying cause in case of endogenous hypercortisolism or reduction of exogenous steroids, as well as physical therapy.

Answer 108

_3 clinically different forms: (1) a slowly progressive infantile/early childhood type, (2) a severe X-linked neonatal type, and (3) an adult-onset type._ _Presents with hypotonia and weakness at birth, or in early childhood, and unlike other forms of congenital myopathy, there is ptosis and ocular palsies, as well as weakness of facial, pharyngeal, laryngeal, and neck muscles. Proximal and distal weakness and hyporeflexia can be seen. Severe forms may be fatal due to respiratory failure in the first few months of life, but in some cases respiratory involvement is mild and/or delayed. Creatine kinase levels are mildly elevated. Needle EMG shows a myopathic pattern with positive waves and fibrillations. Pathologically, there are small muscle fibers and central nucleation, as well as predominance of type I fibers, which are small and hypotrophic._ _Myotubular myopathy is the most common form of centronuclear myopathy and is X-linked. It is typically severe and presents in the neonatal period. The autosomal dominant form is an adult-onset milder form, and the autosomal recessive form is intermediate in severity._

Answer 109

_Age of onset is bimodal for both men and women. For women the peak incidence is at age 20 to 24 and 70 to 75 years, while men have peak incidence at 30 to 34 and 70 to 74 years. In the early-onset group the female to male ratio is 7:3 and in late-onset it is 1:1._

Answer 110

Myasthenia gravis is more common in family members of patients with this disorder. It has been associated with _human leukocyte antigen types B8, DR1, DR2, and DR3_. Patients with myasthenia gravis are at an increased risk of other autoimmune disorders including thyroid disorders, and these should be tested for as clinically indicated.

Answer 111

Over 80% to 85% of patients with myasthenia gravis have acetylcholine receptor antibodies, which have an affinity to the postsynaptic acetylcholine receptor and can be binding, blocking, or modulating. _The most commonly detected are the binding type. These antibodies cause complement-mediated destruction of the junctional folds that contain dense concentrations of this receptor, and a higher rate of internalization and destruction of acetylcholine receptors. Blocking antibodies might block binding of acetylcholine to its receptor at the neuromuscular junction, while modulating bind to a site on the receptor other than the acetylcholine binding site and alter the structure of the active site._

Answer 112

_Edrophonium is an intravenous acetylcholinesterase inhibitor that increases the presence of acetylcholine at the neuromuscular junction (NMJ). In patients with myasthenia, administration of edrophonium leads to transient improvement of weakness within minutes of administration; the edrophonium (Tensilon) test has therefore been used in the diagnosis of myasthenia gravis._

Answer 113

EMG findings in myasthenia gravis include electrodecremental response and jitter. The presence of a 10% or greater decrement in amplitude of a CMAP between the first and fourth to fifth stimuli with repetitive nerve stimulation suggests an NMJ disorder (see Chapter 9). If there is not an abnormality present on repetitive nerve stimulation but there is a high clinical suspicion for myasthenia gravis and it cannot be confirmed with serologic testing, a single-fiber EMG can be performed. Single-fiber EMG is the most sensitive test of NMJ transmission. Jitter is the variability in the measure of interpotential difference between two muscle fiber action potentials during consecutive discharges of the same motor unit. Increased jitter (or increased interpotential time) is present in patients with NMJ abnormalities, but is not specific for myasthenia gravis. Blocking on single-fiber EMG is failure of a single muscle fiber action potential to appear during the motor unit discharge, and occurs when there is significantly increased jitter.

Answer 114

There are three major categories of CMDs _(1) collagenopathies,(2) merosinopathies,_ including laminin-α-2-related CMDs, and (3) dystroglycanopathies

Answer 115

**_AR, 2/2 a mutation of the fukutin gene on chromosome 9q._** Clinical: _weakness and ocular and CNS abnormalities_. Patients are hypotonic and floppy, with joint contractures at the hip, knee, and ankles. The weakness may be generalized, and these patients typically do not learn to walk. Creatine kinase levels are elevated, and muscle biopsy shows dystrophic changes and reduced α-dystroglycan. Central nervous system involvement is common, including cognitive developmental delay and seizures. Brain MRI shows abnormalities in gyration and characteristic white matter changes in the frontal regions.

Answer 116

Dystrophy 2/2 a mutation in the laminin-α-2 gene, which encodes for the protein merosin, immunohistochemical staining of which is thus reduced in muscles of patients with this disease. These patients are hypotonic at birth, and have severe weakness of the trunk and limbs. **Extraocular and facial muscles are spared. Contractures appear in the feet and hips. Some patients may have seizures.** **However, unlike Fukuyama-type CMD, intelligence is generally preserved. MRI shows white matter changes and sometimes cortical abnormalities**

Answer 117

Defined by the occurrence of syncope associated with _either a period of asystole of at least 3 seconds or a fall of at least 50 mm Hg in systolic blood pressure, or both, in response to pressure on the carotid sinus._ In another form of carotid sinus hypersensitivity, hypotension without bradycardia may occur. Triggers can include a tight collar, turning of the head, or even swallowing, though no identifiable triggers may be present. Symptoms and changes in heart rate and/or blood pressure can be reproduced with carotid sinus massage. Treatment is avoidance of triggers, but when recurrent, pacemaker insertion may be necessary. The absence of diaphoresis and nausea, and the presence of bradycardia, hypotension, and triggering by neck turning distinguish this from vasovagal syncope.

Answer 118

The carotid sinus, located at the bifurcation of the common carotid artery, is innervated by a branch of the _glossopharyngeal nerve_. The carotid sinus contains specialized mechanoreceptors that are capable of detecting changes in blood pressure (baroreceptors) and heart rate. With stimulation, either mechanically (with applied pressure) or with elevations in blood pressure, mechanoreceptors send signals to the _nucleus tractus solitarius in the medulla_ leading to a reduction in sympathetic tone (leading to a further reduction in blood pressure) and an increase in parasympathetic tone (leading to a reduction in heart rate). Carotid sinus hypersensitivity results from an exaggerated response to baroreceptor stimulation.

Answer 119

(Glycogenosis type V) Autosomal recessive disorder caused by myophosphorylase deficiency. Myophosphorylase facilitates conversion of glycogen into glucose-6-phosphate; its deficiency will lead to glycogen accumulation/lack of glucose release from glycogen. The typical presentation is exercise- induced weakness and muscle cramps (physiologic contractures: electrically silent when an EMG needle is inserted into the contractured muscles). Unlike normal muscles, when the muscle is exercised there is no production of lactic acid. On exertion, a sensation of fatigue may ensue; however, if the patient slows down or rests briefly, this sensation may disappear and the patient may be able to continue with the exercise. This is called a “second-wind phenomenon,” which is typically seen in McArdle’s disease, and results from mobilization and use of blood glucose.

Answer 120

Tarui disease (glycogenosis type VII) is caused by phosphofructokinase (PFK) deficiency in muscle and erythrocytes. This enzyme participates in the conversion of _glucose-6-phosphate into glucose-1-phosphate_, and therefore, it is similar to _McArdle’s disease from the muscular standpoint. In addition, some patients may develop jaundice (due to hemolysis) and gouty arthritis due to PFK deficiency in erythrocytes_. Immunohistochemical analysis distinguishes these two disorders.

Answer 121

(Glycogenosis type III) is caused by a deficiency in the debranching enzyme, leading to glycogen accumulation. These patients can present with a childhood form with liver disease and weakness or with an adult form characterized by myopathic weakness.

Answer 122

Andersen’s disease (glycogenosis type IV) is caused by a deficiency in the glycogen branching enzyme, and is characterized by hepatomegaly from polysaccharide accumulation, cirrhosis, and liver failure.

Answer 123

Intubation and mechanical ventilation should be initiated when the negative inspiratory force is less than −30 cm of H2O, forced vital capacity less than 15 mL/kg, or if there is a significant downward trend of spirometry measures with clinical evidence of respiratory muscle fatigue.

Answer 124

Medications that exacerbate myasthenia gravis include aminoglycosides, β-blockers, and neuromuscular blocking agents, among others.

Answer 125

_Approximately one-third of patients will have worsening of their myasthenic symptoms at the onset of steroid therapy that lasts up to 10 days_. Therefore, caution is required with the initiation of steroid therapy. When symptoms are severe, and there is concern for significant pharyngeal or respiratory muscle involvement, initiation of plasma exchange or IVIGs prior to starting corticosteroids may be necessary.

Answer 126

Defined by the occurrence of syncope associated with either a period of asystole of at least 3 seconds or a fall of at least 50 mm Hg in systolic blood pressure, or both, in response to pressure on the carotid sinus. In another form of carotid sinus hypersensitivity, hypotension without bradycardia may occur. Triggers can include a tight collar, turning of the head, or even swallowing, though no identifiable triggers may be present. Symptoms and changes in heart rate and/or blood pressure can be reproduced with carotid sinus massage. Treatment is avoidance of triggers, but when recurrent, pacemaker insertion may be necessary.

Answer 127

In general, myofiber necrosis, degeneration, regeneration, increased fiber size variation, endomysial inflammation, and fibrosis are collectively called dystrophic changes, which are characteristic for Duchenne muscular dystrophy, but not specific, and can be seen in other dystrophies.

Answer 128

_A cytoplasmic protein that binds and nteracts with other intracytoplasmic proteins such as F-actin, and is linked to the trans-sarcolemmal dystroglycan protein complex, providing a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix. If dystrophin is lost or altered, this sarcolemmal structure is affected, making it susceptible to rupture._

Answer 129

Muscular dystrophy Becker’s muscular dystrophy is similar to Duchenne muscular dystrophy; however, it is much less severe, with a later onset (usually in adolescence or adulthood)

Answer 130

Myopathy AKA distal myopathy with rimmed vacuoles _AR, GNE gene, chromsome 9_ Clinical manifestations - **onset in early adulthood, foot drop with tibias anterior weakness** that can THEN spread to the arms but with minimal proximal and bulbar involvement Biopsy - _rimmed vacuoles_, EM w/tubular filaments like inclusion body myositis but without inflammation _Vs Welender: AD, also a distal myopathy, but starts first in the arms with o_**_lder age of onset (40-60 years old)_**_, myopathic changes on biopsy with rimmed vacuoles_

Answer 131

**AD, RYR1 gene, chromosome 19** Loss of oxidative activity within the center of muscle fibers, that span along length of muscle fiber (vs multicore or minicore disease where there is only loss in segments), _see on NAD stain as paler areas in center, where there is absence of mitochondria_ At risk for malignant hyperthermia, consider when general anesthesia is needed. S(x)s: weakness and hypotonia soon after birth, subsequent delay in motor development. The weakness is predominantly proximal, and the pelvic girdle is usually more affected than the shoulder girdle. _Facial, bulbar, and ocular muscles are usually spared_. Creatine kinase levels are slightly elevated.

Answer 132

AKA acute pandysautonomia, caused by _S(x)s over weak vs pure autonomic failure, where s(x)s develop slowly over time_ S(x)s mixture of parasympathetic and sympathetic dysf(x): orthostatic hypotension, absent heart rate variability (see question 47 on tilt table testing), hypohidrosis or anhidrosis, dry mouth and eyes, pupillary abnormalities, sexual dysfunction, early satiety, constipation, and diarrhea due to abnormal gastric and intestinal motility. _½ patients w/ antibody against the ganglionic nicotinic acetylcholine receptor can be identified in the serum._ Can be AI or paraneoplastic (a/w SCLC), with antibody in either form. AI can be associated with either AI conditions or preceding illness. Tx: plasma exchange and intravenous immunoglobulins; typically, some improvement of symptoms occurs, but full recovery is unlikely.

Answer 133

_Anti-striational muscle antibodies can be detected in patients with autoimmune myasthenia gravis or thymoma._

Answer 134

Myopathy _AR_: gene encoding _dysferlin on chromosome 2p (also ANO5)_ S(x)s: early in adult life, weakness and atrophy _in the distal leg muscles, predominantly in the posterior compartment_. Creatine kinase levels are markedly elevated in the range of 10 to 100 times that of normal. Biopsy shows dystrophic changes. Vs (Gower-) Laing myopathy: _AD also distal myopathy but begins in the anterior tibial compartment + neck flexors._ Eventually, finger extensors, shoulder and hip girdle muscles can become involved; finger flexors and hand intrinsic muscles are spared. The disorder is related to a mutation in myosin heavy chain gene (**_MyH_**_C 1 or_ **_MYH_**_7,_ **_Chromosome 14_**_)_.

Answer 135

_In patients with anti-MuSK antibodies, the clinical picture may resemble the typical form of autoimmune myasthenia gravis or ocular myasthenia, but more commonly, weakness involves predominantly cranial and bulbar muscles, with prominent dysphagia, neck flexor weakness, and respiratory weakness, with relative sparing of ocular muscles (though eyelid and ocular muscle involvement may occur). This disorder is more common in young women, and typically does not respond to_ **_pyridostigmine._** _Treatment is with immune-modulating therapy, including intravenous immunoglobulins and plasmapheresis._

Answer 136

AR In utero - may be decreased movements. At birth, hypotonic and weak, with arthrogryposis, and may develop respiratory insufficiency and bulbar dysfunction. With time, contractures and scoliosis. These patients also have developmental delay and developmental anomalies of the cerebral cortex. Seizures occur in some subtypes of these disorders. Creatine kinase is markedly elevated. EMG shows myopathic changes. Histopathologically, there are dystrophic changes with degeneration and regeneration of muscle fibers, and infiltration of connective tissue. The congenital muscular dystrophies are caused by genetic defects in sarcolemmal membrane proteins or membrane-supporting structures.

Answer 137

The use of methotrexate should be avoided if patients have interstitial lung disease because this medication can be toxic to the lungs.

Answer 138

An inflammatory condition of the muscle with skin findings. The muscle weakness is a typical myopathic weakness, predominantly proximal - ing unable to stand from the sitting position, inability to walk up stairs, and difficulty lifting their arms above their head. Skin findings: heliotrope rash (purplish discoloration of the eyelids), erythema of the face, neck, anterior chest, upper back, elbows and knees, Gottron’s papules (purplish scaly papular rash on the extensor surface of the hands), and “mechanic’s hands” (thickened skin on the dorsal and ventral surface of the hands). _CK: Normal or elevated_ _Characteristic biopsy finding: perivascular inflammation_ _Associations: 1.) Malignancy - patients should have age-appropriate malignancy screening. 2.) with interstitial lung disease, especially if the anti-Jo antibody +. Anti-Jo antibodies occur more commonly in polymyositis than dermatomyositis but can occur in either condition_. Treatment: Steroids → Azathioprine, MTX but be careful with MTX in the case of interstitial lung disease

Answer 139

AKA Bradbury–Eggleston syndrome _Secondary to loss of intermediolateral cell column neurons from deposition of α-synuclein in the autonomic nervous system._ Prsentation: mid to late adulthood. In men, the earliest symptom is typically impotence. Orthostatic (postural) hypotension (defined as a reduction of systolic blood pressure by 20 mm Hg or diastolic blood pressure by 10 mm Hg, or both), or a pulse rate increase of 20 bpm, is present, and is often worse in the morning, after meals, exertion, and with heat exposure. Supine hypertension may occur as well. Other features include hypohidrosis, nocturia, early satiety and nausea (due to gastrointestinal hypomotility), urinary hesitance and/or urgency with occasional incontinence, and neck and shoulder aching (“coat hanger” distribution) precipitated by standing.

Answer 140

_An inflammatory condition of the muscle in which there are no skin findings. The weakness is proximal._ _Associations: With interstitial lung disease, and anti-Jo antibody may be a marker of this association. On the other hand, polymyositis as opposed to dermatomyositis does not have a strong correlation with the presence of malignancy._ _A subset of patients with polymyositis has antibodies to various muscle components, including antibodies against cytoplasmic transfer ribonucleic acid (tRNA) synthetases (anti-Jo 1), or against the tRNA itself. These antibodies occur in both polymyositis and dermatomyositis, but are more common in polymyositis._

Answer 141

Lipid-lowering agents that inhibit HMGCR. Muscle toxic effects: possible mechanism of _this adverse effect via action on the mitochondria and sarcoplasmic reticulum, especially in type II muscle fibers. A mutation in the gene SLCO1B has been associated with predisposition to develop statin-induced myopathy (LDL receptor gene mutations cause disorders of lipid metabolism, which statins are used to treat)._ Manifestations: _1.) Increased serum creatine kinase (CK) in entirely asymptomatic patients, with mild elevations and rarely up to 10 times the upper limit of normal_. 2.) _Myalgia with or without increased serum CK levels. Usually muscle strength is preserved, and myalgia may improve with stopping the medication_. 3.) _Muscle weakness with serum CK elevation._ 4.) Rhabdomyolysis. CK levels are markedly elevated, sometimes above 15,000 IU/L (normal up to 220 IU/L) → myoglobinuria and renal failure. _5.) Necrotizing autoimmune myopathy (NAM). Usually characterized by a rapid onset of severe proximal weakness, and CK levels of typically over 6,000 IU/L_. Weakness is progressive with rising CK levels despite discontinuation of statin. _Antibodies against HMGCR have been implicated in the pathogenesis of this disease. This is an aggressive myopathy and needs to be treated with immunosuppressive agents. NAM can also be associated with antibodies against signal recognition peptide (SRP)_

Answer 142

Myotoxicity with statins increases with _higher cholesterol- lowering potency of the statin, with higher statin dosages, and for statins with higher lipophilicity (the lipophilic statins include atorvastatin, lovastatin, and simvastatin, whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic)._ Concomitant use of fibrates can increase the risk of developing muscle toxicity. There can also be increased risk by the use of other drugs, such as azole antifungals, macrolides antibiotics, antiretrovirals, and amiodarone, among others

Answer 143

_In POTS, tilt table examination shows an increase in heart rate of at least 30 bpm from baseline, or more than 120 bpm within 10 minutes of head-up tilt, without significant changes in blood pressure,_ but with symptoms of orthostasis such as light- headedness, palpitations, generalized weakness, visual changes, headache, or tremor. MC in females, tends to triggered by menses suggesting a possible role for estrogen. Symptom onset may follow a variety of triggers, including viral infection, pregnancy, or surgery, and for this reason, autoimmune causes have also been postulated. Rarely a manifestation of a mutation in a norepinephrine transporter gene, which leads to elevated plasma levels of norepinephrine, with subsequent sympathetic overactivity. In others, treatment may include β-blockers, increased fluid and salt intake, fludrocortisone, and midodrine. Vs vasovagal and orthostatic hypotension - _There is not a reduction in blood pressure in POTS, distinguishing it from orthostatic hypotension. With vasovagal response, there is no tachycardia but rather transient bradycardia due to parasympathetic overactivation_.

Answer 144

_Adult-onset periodic paralysis suggests a possible secondary cause, of which thyrotoxic periodic paralysis is the best recognized._ _Thyrotoxic periodic paralysis is a condition associated with hyperthyroidism, thought to be present in genetically susceptible patients but without a known gene mutation detected to date. It is more common in Asians, with a male predominance. These patients have episodes of proximal weakness and other manifestations of thyrotoxicosis. During acute attacks, potassium should be provided. β-blockers may be of benefit as prophylaxis. Carbonic anhydrase inhibitors (for hypokalemic periodic paralysis) do not work._

Answer 145

_Adult onset \>50 years old. IBM is the most common inflammatory myopathy in individuals older than 50 years. Affects men \> women in 3:1 ratio_ _Asymmetric painless weakness and atrophy more proximal in the arms and proximal and distal in the legs._ Involves the wrist and finger flexors, adriceps, and anterior tibial muscles. Involvement of the finger flexors and flexor pollicis longus, leading to thumb flexion weakness, with relative preservation of finger abductors (the dorsal interossei) is a classic finding of IBM. In contrast to dermatomyositis and polymyositis, deltoid strength is typically preserved in IBM. Dysphagia can be present, and there are no skin manifestations (distal weakness into arms and proximal in the legs). Creatine kinase may only be slightly elevated. This condition does not respond to steroids, and effective therapies are currently not available.

Answer 146

Group of muscular dystrophies in which there is proximal weakness with involvement of the shoulder or pelvic girdle with sparing of the facial muscles. It can present in both sexes, and the inheritance is either autosomal dominant or recessive. _LGMD1 is autosomal dominant and LGMD2 is autosomal recessive_. Needle EMG shows myopathic changes. Muscle biopsy shows dystrophic changes, with myofiber necrosis, degeneration, regeneration, increased fiber size variation, endomysial inflammation, and fibrosis. Treatment: Associated with joint contractures, and early intervention with physical and occupational therapy to prevent contractures and preserve mobility and function is recommended (strength and aerobic training are not harmful and may be of benefit). Recommended that pulmonary function testing occur once at diagnosis, and periodically on follow-up. Some types of LGMD are associated with oropharyngeal dysphagia, feeding tubes and other means of nutrition should be instituted as needed. NO gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment.

Answer 147

AD Includes genes from Emery-Dreyfuss

Answer 148

AR Include genes for Nonaka and Miyoshi

Answer 149

_Results from antibodies against presynaptic P/Q- type voltage-gated calcium channel, reducing the influx of calcium that normally leads to release of acetylcholine into the NMJ_. _Vs autoimmune myasthenia gravis, less likely to involve ocular or bulbar musculature; it predominantly affects proximal (shoulder and hip girdle) and trunk musculature. Proximal leg weakness is a common clinical presentation of LEMS. The weakness perceived by the patient may be out of proportion to the examination._ While in LEMS, worsening of muscle weakness with repetitive muscle use ultimately occurs, there is a transient improvement of muscle strength following repetitive muscle use prior to worsening weakness. This can sometimes be elicited on physical examination as well as electrophysiologically. _Also, unlike myasthenia gravis, in LEMS, deep tendon reflexes are often diminished or absent. Autonomic features are prominent in LEMS, including constipation, urinary retention, and impotence._ MC in males, may be AI or paraneoplastic, MC paraneoplastic - SCLC, requires cancer screening, the SOX antibody has been identified as being a useful marker to distinguish between squamous cell lung cancer–associated paraneoplastic LEMS (in which SOX antibody is present) and autoimmune LEMS. Patients with LEMS respond little if at all to acetylcholinesterase inhibitors. _Symptomatic treatment of LEMS may be achieved with 3,4-diaminopyridine (3,4-DAP), a drug that inhibits presynaptic potassium channels, prolonging depolarization and increasing acetylcholine vesicle exocytosis_. Autoimmune LEMS is treated with immunosuppressive therapy, including _corticosteroids as well as steroid-sparing agents, intravenous immunoglobulins, and plasmapheresis._ Response to these treatments is variable and is typically not as successful as in myasthenia gravis. In paraneoplastic LEMS, treatment of the malignancy may improve the neuromuscular symptoms.

Answer 150

EMG shows low-amplitude CMAPs that increase in amplitude following brief exercise _( in which there is a \>50% increase in CMAP amplitude post exercise)_. This is a phenomenon known as facilitation. On high-frequency repetitive nerve stimulation, a prominent increment is seen, in contrast to the electrodecrement seen with low-frequency repetitive nerve stimulation in myasthenia gravis.

Answer 151

_2/2 intestinal nematode Trichinella, transmitted by the ingestion of uncooked pork with encysted larvae_. Once ingested,. _The female worms deposit batches of larvae in the intestinal wall, which migrate via lymphatics into the bloodstream. These larvae invade all tissues, but survive only in muscles, where they become encysted and calcify._ S(x)s: _mild gastroenteritis on ingestion of infected meat → 1 - 4 to 6 weeks later: low-grade fever, myalgias, fatigue, and edema of the conjunctiva and eyelids. Ocular muscle weakness occurs → strabismus and diplopia. Weakness of the tongue and masticatory as well as pharyngeal muscles occurs → dysarthria and dysphagia. Limb muscle weakness occurs, more prominent proximally. The diaphragm and cardiac muscles may also be involved_. Myopathic symptoms eventually subside and patients generally improve completely. However, massive infections have been reported to cause CNS symptoms, including headaches, neck stiffness, and confusion. Laboratory studies demonstrate _eosinophilia and moderate elevations of CK. Enzyme-linked immunosorbent assay blood test for trichinella becomes positive after 1 to 2 weeks and may be helpful._ _Muscle biopsy will demonstrate the parasite and sometimes an inflammatory infiltrate with eosinoph_ils. Treatment includes a combination of thiabendazole with steroids. Thiabendazole is an antihelminthic that prevents larval reproduction and interferes with the metabolism of the larvae in the muscle. Albendazole is also effective.

Answer 152

Phenotypic variability, with presentations ranging from severe neonatal congenital forms to adult-onset forms in which patients have proximal weakness, cardiomyopathy, and prominent compromise of respiratory muscles. Neonatal forms present with dysmorphic features, contractures, arthrogryposis, generalized hypotonia, feeding difficulties, and respiratory problems. There are other intermediate forms with infantile-onset, childhood- and adolescent-onset forms. It can be caused by mutations in several genes that encode for various muscle proteins such as α-actin, α-tropomyosin, and _β- tropomyosin, nebulin, troponin, and cofilin_. _Histopathologically, the fibers have rod-like structures that are seen beneath the sarcolemma, also known as nemaline bodies or nemaline rods. Type I fibers are smaller than normal and predominate._

Answer 153

Upright tilt table evaluation is used to obtain objective measures of blood pressure and heart rate in various postures. In normal individuals, during the tilt table test, at 60 to 80 degrees of tilting for 10 minutes, there is a brief 5 to 15 mm Hg reduction in systolic blood pressure, a 5 to 10 mm Hg increase in diastolic blood pressure, and a 10 to 15 bpm increase in heart rate. If there is early, gradual, and sustained hypotension (\>20 mm Hg reduction in systolic blood pressure) without compensatory tachycardia, this is an indication of insufficient sympathetic tone and impaired baroreceptor function. Hypotension with compensatory tachycardia suggests hypovolemia. If hypotension is delayed for several minutes but then occurs abruptly with bradycardia, this is more suggestive of a neurocardiogenic mechanism. Most neurogenic causes of syncope lead to hypotension that occurs within the first 5 to 10 minutes of tilting, without a compensatory tachycardia.

Answer 154

The thermoregulatory sweat test is a test of sudomotor function; it is a qualitative test of sweating in which an indicator powder is applied to the subject who is then exposed to elevated temperatures. Sweat interacts with the powder, and the distribution pattern of the powder indicates areas of normal sweating and identifies areas of absent or reduced sweating. _Different patterns of hypo- or anhidrosis can be identified that correspond to different autonomic disorders. In large and small fiber neuropathies, distal anhidrosis occurs. In patients with multiple system atrophy, pure autonomic failure, and autonomic neuropathies, global hypohidrosis or anhidrosis occurs._

Answer 155

The quantitative sudomotor axon reflex test is another test of sudomotor function. A sweat cell is applied to the skin and an electric current is then applied. Acetylcholine is iontophoresed into the skin, stimulating sweat glands. Sweat production is measured from adjacent sweat glands that are stimulated via an axon reflex. _If there is a low or absent response following application of the electric current, this indicates a lesion of the postganglionic sympathetic axon._

Answer 156

AR, deficiency of the lysosomal enzyme acid maltase (also known as α-1,4-glucosidase). This enzyme participates in the breakdown of glycogen to glucose; its deficiency leads to glycogen accumulation, causing the typical histopathologic findings on muscle biopsy: vacuolated sarcoplasm with glycogen accumulation that stains strongly with acid phosphatase. There are three forms of acid maltase deficiency: 1.) Pompeii's disease: infantile form presenting in first few months of life with difficulty feeding, cyanosis, dyspnea, macroglossia, hepatomegaly, cardiomegaly, and hypotonic weakness. This form _progresses rapidly and patients die in the first few months_. 2.) Childhood form, which has an onset in the second year of life, manifests with proximal weakness, motor developmental delay, hypotonia, enlarged calves, and r_arely with cardiomegaly, hepatomegaly, and mental retardation._ These patients may die of pulmonary infections and respiratory failure. 3) _Adult form, which presents in the second to fourth decades of life, manifests with slowly progressive proximal weakness and typically weakness of the diaphragm, leading to neuromuscular respiratory problems. These patients do not typically have cardiomegaly, hepatomegaly, or mental retardation._

Answer 157

Genetically heterogeneous group of NMJ disorders Most commonly present at birth but some not until childhood/early adulthood. MC in males. _The typical presentation is one of ophthalmoparesis and ptosis in infancy, with facial diparesis._ Limb weakness and hypotonia are often present, and respiratory involvement is rare but can occur. As in autoimmune myasthenia gravis, in some forms of congenital myasthenia, intravenous administration of edrophonium (a peripheral reversible acetylcholinesterase inhibitor) transiently improves symptoms, and there is symptomatic benefit from oral acetylcholinesterase inhibitors as well. _Because the congenital myasthenic syndromes are not immune-mediated, there is no response to immunosuppressive therapy or thymectomy._ Electrophysiologic findings are similar to other neuromuscular disorders, showing a decremental response on repetitive nerve stimulation studies and increased jitter on single-fiber EMG. The most common form of congenital myasthenia, congenital acetylcholine receptor deficiency, is due to an autosomal recessive or sporadic mutation in the acetylcholine receptor gene. Acetylcholinesterase deficiency is another congenital myasthenic syndrome that presents with axial and respiratory weakness in early infancy. Characteristically, patients have a delayed pupillary response to direct light. Due to deficiency of the enzyme, these patients do not respond to acetylcholinesterase inhibitors such as edrophonium or pyridostigmine.

Answer 158

Presentation: Neonatal weakness, contractures and distal hyperlaxity, as well as protrusion of the calcanei. Mutations in the collagen type VI gene

Answer 159

Divided into cranial and sacral portions: A.) Cranial portions - originate in brain stem nuclei and are relayed to their target sites via four cranial nerves: (1) oculomotor, (2) facial, (3) glossopharyngeal, and (4) vagus. 3.) Sacral portions - Cells located in S2 to S4 of the spinal cord give rise to the sacral portion of the parasympathetic nervous system and innervate the genitourinary system and distal colon. The neurotransmitter for all sympathetic and parasympathetic preganglionic fibers is acetylcholine that acts at nicotinic receptors in the ganglia. Parasympathetic postganglionic neurons predominantly release acetylcholine. Parasympathetic preganglionic/NMJ - nicotinic Parasympathetic postganglionic - muscaranic In the parasympathetic nervous system, the ganglia are located close to the target site, with long preganglionic fibers and short postganglionic fibers.

Answer 160

The intermediolateral cell column of the spinal cord, present from T1 to L2, contains the preganglionic neurons of the sympathetic nervous system. * Small myelinated preganglionic fibers known as white rami communicantes exit the intermediolateral cell column and synapse on sympathetic ganglia located in the paravertebral region. * _Postganglionic fibers known as gray rami communicantes are carried through spinal nerves T1 to T4 to supply thoracic regions and T5 to L2 to supply various subdiaphragmatic end organs including blood vessels, gastrointestinal organs, and genitourinary tract_ The neurotransmitter released from postganglionic sympathetic fibers is norepinephrine, except in sweat glands, where acetylcholine is released and acts at muscarinic receptors. In the sympathetic nervous system, preganglionic fibers are short and postganglionic fibers are long.

Answer 161

Carried by C8-T2

Answer 162

Secondary to a lesion in the sympathetic pathways. The sympathetic tracts originate in the hypothalamus and descend in the lateral brain stem to synapse with sympathetic neurons in the intermediolateral cell column in the spinal cord that is present from spinal segment T1 to L2. The face receives sympathetic innervation from intermediolateral cells at the C8 to T2 level. Preganglionic fibers synapse in the superior cervical ganglion. Postganglionic fibers travel along the common carotid artery. * _At the carotid bifurcation, fibers to the sphincter pupillae of the eye travel with the ICA, and are involved in pupillary dilation. Fibers to Muller's smooth muscles in the upper eyelid are also carried along this route._ * _Sympathetic fibers destined for the eccrine glands of the face travel along the ECA._

Answer 163

Ptosis, miosis, anhidrosis Features include ptosis, due to loss of innervation of Muller’s smooth muscle, miosis, due to loss of innervation of the pupillary dilator muscle, a_pparent enophthalmos, due to lack of input to the lid retractors (the eye appears sunken, though it is not)_, and loss of ciliospinal reflex (absence of pupillary constriction when painful stimulation is applied to the cervical region ipsilateral to the lesion). Preganglionic lesions (medullary infarction, during thoracotomy, or with large lung masses) that impinge on the preganglionic fibers as they make their way to sympathetic cervical ganglion cause triad of ptosis, mitosis, and anhidrosis; lesions in the region of the ICA (such as ICA dissection) spare the fibers destined for the eccrine glands of the face (traveling with the ECA), and anhidrosis does not occur.

Answer 164

The ptosis and pupillary abnormalities seen in Horner’s syndrome can be distinguished from a third nerve palsy by the presence of intact extraocular movements of cranial nerve III- innervated muscles (medial rectus, inferior oblique, superior rectus, and inferior rectus). _In addition, with loss of sympathetic innervation to the pupil, the anisocoria will be more prominent in dim light, as the contralateral (normal) eye will normally dilate, whereas the eye that has lost sympathetic innervation will remain miotic. The miotic eye will still normally constrict to light and accommodation (because parasympathetics are not impaired)._

Answer 165

Penile erection is mediated by the parasympathetic nervous system and ejaculation by the sympathetic nervous system. _Penile erection is mediated by parasympathetic fibers derived from S3 and S4 and carried by the pudendal nerve. Ejaculation is a sympathetically mediated reflex arc: the afferent pathway is via the dorsal nerve of the penis and pudendal nerve to S3 and S4, and the efferent pathway includes the perineal branch of the pudendal nerve._ A common way to remember this innervation is “Point (Parasympathetics cause erection) and Shoot (Sympathetics cause ejaculation).”

Answer 166

_In detrusor sphincter dyssynergia, the detrusor muscle contracts against an unrelaxed urethral sphincter_

Answer 167

Under sympathetic control

Answer 168

Both voluntary and involuntary components * Voluntary contraction of the external urethral sphincter is mediated by sympathetic innervation derived from the intermediolateral cell column in the spinal cord at the level of L1 and L2 * Involuntary control of the detrusor muscle - The pontine micturition center regulates the detrusor reflex. Nerve roots S2 to S4 relay afferent sensory information from the genitourinary system, bladder, and anorectal area to the spinal cord. Onuf’s nucleus at S2 to S4 contains the cell bodies of neurons that control the urethral and anal sphincters. Somatic efferents to the skeletal muscles of the pelvic floor arise from these cells and are carried by the pudendal nerves. Normally, individuals are able to maintain voluntary control over micturition through the medial frontal micturition centers located in _the paracentral lobules (the medial continuation of the precentral gyrus_). At the initiation of voluntary micturition, the detrusor reflex, which is mediated by spinal cord circuits, is initiated by voluntary external urethral sphincter relaxation and involuntary relaxation of the internal urethral sphincter with detrusor contraction. _If the external urethral sphincter is voluntarily contracted during micturition, the detrusor muscle involuntarily relaxes and micturition stops._

Answer 169

_With lesions of the cauda equina, a flaccid bladder results from loss of detrusor tone, sensation of bladder fullness is lost, and voluntary control over urination is lost._ Overflow incontinence may occur; these patients often require intermittent self-catheterization chronically.

Answer 170

Voluntary control over the external urethral sphincter is lost.

Answer 171

Lesions above the conus medullaris lead initially to a flaccid bladder leading to urinary retention with or without overflow incontinence. Some time after a spinal cord lesion, the bladder may become hyperreflexic. Urge incontinence results from overactive detrusor contraction; this is a frequent occurrence in patients with multiple sclerosis, though flaccid bladder with requirements for intermittent catheterization can also occur.

Answer 172

The enteric nervous system consists of the myenteric (or Auerbach’s) plexus that is located between the outer and inner smooth muscle layers of the gastrointestinal tract and the submucous (or Meissner’s) plexus, which is located between the circular muscle layer and the mucosa. The myenteric plexus is predominantly involved in gut motility, whereas the submucous plexus is involved in secretory functions. Together, the myenteric and submucous plexus control the function of the gastrointestinal tract.

Answer 173

Due to congenital absence of the myenteric plexus. Most commonly, focal congenital absence of the myenteric plexus in the internal anal sphincter or rectosigmoid junction occurs, though in rare cases, the myenteric plexus may be absent throughout the gastrointestinal system. Segments of the colon that lack myenteric plexus cannot relax, leading to fecal retention and distention of proximal colonic segments. Some cases of Hirschsprung’s disease are due to mutations in the RET proto-oncogene.

Answer 174

Muscular dystrophy - causative mutations in genes forproteins myotilin, desmin, and αβ-crystallin. May be autosomal dominant or recessive, and affects males and females equally. It is characterized by slowly progressive weakness of the muscles of the limbs and trunk, affecting both proximal and distal muscles, but more the lower than the upper extremities. Cardiac involvement with conduction abnormalities is present in about 25% of the cases, and peripheral neuropathy can also be seen. Hyporeflexia is frequent. Pathologically, there is focal dissolution of myofibrils and subsarcolemmal accumulation of dense granular and filamentous material, variation of fiber sizes, rimmed vacuoles, and central nucleation.

Answer 175

CIM can occur independently or in combination with critical illness polyneuropathy (CIPN). _The typical presentation is a flaccid weakness, which is diffuse and involves not only limb muscles but also the diaphragm, making these patients difficult to wean from mechanical ventilation._ _Systemic inflammatory response syndrome, and with risk factors including hyperglycemia, hypoalbuminemia, sepsis, exposure to steroids, neuromuscular blocking agents, and certain antibiotics._ Electrophysiologic studies show SNAPs greater than 80% of the lower limit of normal and low-amplitude CMAPs, as well as myopathic findings on needle EMG. Pathologically, there is type II fiber atrophy and characteristic loss of thick myosin filaments. _Because muscle regeneration is much faster than nerve regeneration, CIM improves earlier._

Answer 176

Similar risk factors as described above for CIM, and is characterized by the presence of axonal degeneration of motor and sensory fibers, as detected electrophysiologically by BOTH low SNAPs and CMAPs. Needle EMG may demonstrate neurogenic changes.

Answer 177

Autosomal dominant condition associated with mutations affecting the gene encoding collagen type VI. These patients present with weakness and contractures of the elbow and ankles, as well as hyperextensible interphalangeal joints.

Answer 178

Associated with anti-(HMGCoA) reductase and anti-SRP antibodies For necrotizing myopathies associated with SRP: * Presence of anti-SRP antibodies is often associated with statin use, though in such cases, the muscle pathology has been attributed to autoantibody-mediated processes rather than direct toxic effects of the statin on the muscle. Thus, discontinuation of the statin does not typically lead to resolution of the signs/symptoms. * Can also occur in the absence of statin exposure, and in such cases may be either a primary autoimmune process or associated with underlying malignancy. * _In anti–SRP- associated necrotizing myopathy, myonecrosis but with little or no evidence of inflammation may be seen. EMG shows fibrillation potentials at rest, increased insertional activity, short-duration polyphasic potentials, and spontaneous and positive sharp waves. Treatment is with immunosuppression._

Answer 179

Nonpharmacologic measures include _(i) lower extremity compression stockings which reduce venous pooling of blood in the legs, and abdominal binders which help redistribute blood from the splanchnic mesenteric circulation to the systemic circulation. (ii) The patient is encouraged to increase fluid intake and ingest salt liberally._ (iii) To decrease nocturnal hypertension (from pharmacologic therapies) and to reduce nocturnal diuresis, _it is recommended that patients place a wedge under the head of their mattress bed during sleep._ Pharmacologic treatment options include _(i) midodrine, a vasopressor, (ii) pyridostigmine, a cholinesterase inhibitor which increases acetylcholine and acts at nicotinic ganglionic receptors, (iii) fludrocortisone, a mineralcorticoid which expands plasma volume and increases vascular α-receptor sensitivity, (iv) droxidopa, which is converted to norepinephrine._ All the pharmacologic agents, with the exception of pyridostigmine, can lead to significant supine hypertension.

Answer 180

Paraneoplastic autonomic ganglionopathy antibody with ganglionic nicotinic acetylcholine receptor

Answer 181

Lesion distal to carotid bifurcation, as sweat fibers travel along the external carotid

Answer 182

Absent dystrophin, XLR

Answer 183

Glossopharyngeal neuralgia

Answer 184

POTs, MC form of dysautonomia

Answer 185

LMNA, AD Emerin, X-lined

Answer 186

Central pale cores in NADH stains from absence of mitochondria Associated with malignant hypothermia

Answer 187

Glycogen storage disease VII AR, PFK deficiency

Answer 188

Maldevelopment with focal absence of the myenteric plexus, sometimes due to the RET proto-onco gene

Answer 189

Abnormal or reduced dystrophin, XLR

Answer 190

Glycogen storage disease III AR, Debranching enzyme deficiency

Answer 191

Carotid sinus hypersensitivity

Answer 192

_50% of seronegative myasthenia's, predominantly involving swallowing, neck flexors_

Answer 193

Glycogen storage disease V AR, Deficiency in myophosphorylase: facilitates conversion of glycogen into glucose-6-phosphate

Answer 194

Perifasicular atrophy

Answer 195

AD, CTG repeat in DMPK gene

Answer 196

Glycogen storage disease II AR, Acid maltase deficiency

Answer 197

Autosomal domiant GCN (A/T/G/C) repeat, PABP2 gene

Answer 198

AD, CCTG repeat, zinc finger protein gene

Answer 199

Rimmed vacuoles

Answer 200

Myosin loss

Answer 201

Glycogen storage disease IV AR, branching enzyme

Answer 202

This tends to occur most frequently in patients who present with bulbar-onset ALS. On the other hand, a subset of patients presenting with FTD have clinical and electrodiagnositic features of motor neuron disease. The pathology of patients with so-called ALS-FTD includes atrophy in the frontal and temporal lobes and ubiquitin-positive, TDP-43–positive, tau-negative inclusions. Autosomal dominant forms have been linked to TDP-43 gene mutations on chromosome 9. **The C9orf72 mutation on chromosome 9 is likely the most common cause of familial FTD- ALS.**

Answer 203

* Parotid and submandibular botulinum toxin injections are effective in some patients with ALS with refractory sialorrhea, and should be offered when appropriate. * The majority of patients experience hypoventilation, and orthopnea becomes significant in advanced stages. Nocturnal oximetry, supine forced vital capacity, and supine maximal inspiratory pressure should be periodically assessed in ALS patients. Noninvasive ventilation should be offered as indicated, and likely improves quality of life. * Frequent evaluation of swallowing function is important as ALS patients are at increased risk of aspiration. Placement of a percutaneous gastrostomy (PEG) tube stabilizes body weight and maintains hydration in ALS patients; although survival is probably not prolonged significantly, quality of life is improved. * Pharmacologic treatment of ALS may include riluzole, an inhibitor of glutamate release, which slows disease progression, prolonging survival by approximately 3 months. * Dextromethorphan–quinidine combination is used for the treatment of pseudobulbar affect. * Management of ALS patients in multidisciplinary clinics, including experts in neurology, speech therapy, physical and occupational therapy, respiratory therapy, social work, and case management is likely of benefit.

Answer 204

Pharmacologic treatment of ALS may include riluzole, an inhibitor of glutamate release, which slows disease progression, prolonging survival by approximately 3 months. Patients may experience side effects of dizziness, fatigue, and gastrointestinal upset, which are usually mild and transient; if intolerable, dosage can be reduced or taken with food prior to deciding to discontinue it. Importantly, blood counts and liver enzymes should be checked routinely 1 month after beginning riluzole, monthly for 3 months, then every 3 months for the rest of the first year, and yearly afterward.

Answer 205

Vitamin B12 as methylcobalamin is a cofactor for the enzyme methionine synthase in t_he conversion of homocysteine to methionine, which is then adenylated to S-adenosylmethionine. S- adenosylmethionine is required for methylation reactions, and decreased levels may lead to reduced myelin basic protein methylation and white matter vacuolizatio_n. Methionine also facilitates the formation of _formyltetrahydrofolate, which is involved in purine and pyrimidine synthesis, and therefore low methionine levels secondary to vitamin B12 deficiency impair DNA synthesis._ In another pathway, vitamin B12 as adenosylcobalamin is a cofactor in the conversion from methylmalonyl CoA to succinyl-CoA. Vitamin B12 deficiency will lead to the accumulation of methylmalonate and propionate, providing abnormal substrates for fatty acid synthesis, and therefore interfering with myelin synthesis.

Answer 206

Malabsorption is the most common cause of vitamin B12 deficiency, and _achlorhydria in the setting of pernicious anemia is an important cause. Pernicious anemia is an autoimmune condition in which anti-intrinsic factor and antiparietal antibodies may be present. Given that these patients have achlorhydria, gastrin levels may be elevated as well._ Parenteral vitamin B12 supplementation is the treatment of choice in cases of malabsorption, and usually the hematologic abnormalities improve rapidly. _However, the neurologic manifestations may not resolve completely. Vitamin B12 levels rise with treatment, regardless of the clinical effect, therefore MMA and homocysteine levels should be followed._

Answer 207

_Tropical spastic paraparesis due to human T-lymphotropic virus type 1 (HTLV-1) typically occurs in endemic regions (equatorial and South Africa, the Caribbean, parts of Asia, Central and South America) and rarely in the United States._

Answer 208

Group of disorders characterized by progressively worsening spasticity of the lower extremities, with variable weakness and difficulty walking. * Pure form: only with lower extremity spasticity * Complicated form: + optic neuropathy, deafness, amyotrophy, peripheral neuropathy, ataxia, dementia, mental retardation, and extrapyramidal dysfunction. It is inherited most commonly in an **autosomal dominant** fashion, but it can occur in an autosomal recessive fashion, while X-linked and sporadic cases have also been reported * _Most common associated mutation: SPAST gene on chromosome 2p22_ * Other proteins involved include atlastin, paraplegin, spartin and maspardin, among others. The treatment is symptomatic, with pharmacologic treatment of the spasticity, and supportive care for the disability.

Answer 209

Syphilis, viruses such as herpes zoster and HTLV-1 (causes tropical spastic paraparesis or HTLV-1 associated myelopathy) , mycobacteria, and fungal agents. However, the most common cause of spinal cord involvement in HIV patients is primary HIV-related myelopathy.

Answer 210

_HIV-related (micro)vacuolar myelopathy presents in patients with AIDS and is a late manifestation; affected patients have gradually progressive gait difficulty, spasticity, leg weakness, and impaired proprioception. There is no back pain and the upper extremities are typically spared. MRI reveals spinal cord atrophy, but more often is normal._ There is no effective treatment, and the initial goal is prevention with antiretroviral therapy.

Answer 211

This is a chronic progressive myelopathy endemic in equatorial and South Africa, as well as in parts of Asia, Central and South America, and the Caribbean. This virus can be transmitted via contaminated blood, sexual activity, breastfeeding, and rarely in utero. Only 1% to 2% of infected individuals will develop neurologic disease. These patients will manifest with a slowly progressive spastic paraparesis, lower extremity paresthesias, painful sensory neuropathy, and bladder dysfunction. MRI reveals increased signal on T2-weighted images with atrophy of the **thoracic cord (where disease burden is greatest)**, but these findings are not specific for this condition. The diagnosis is made with positive serology in blood and CSF to HTLV-1, as well as PCR of the virus. No antiviral agent is available at this moment for the treatment of HTLV-1. This virus is also associated with adult T-cell lymphoma and leukemia \*\*\*HTLV-2 is also associated with a progressive myelopathy and can be seen in native Americans, IV drug users, and patients with HIV, but this is much less common than HTLV-1.

Answer 212

Involves upper extremities with predominant LMN findings

Answer 213

The area of the spinal cord most susceptible to watershed infarcts is at the **upper-mid thoracic levels (between T4 to T8),** given that blood supply is scarce between blood supply coming from the vertebral circulation and the aortic circulation, though watershed infarcts at lower levels have been described. Patients with vascular risk factors for atherosclerotic disease are at higher risk for developing this type of spinal cord infarct.

Answer 214

_Unlike PMA, which progresses, on average, over 3 to 5 years, adult-onset spinal muscular atrophy is even more indolent and_ **_often affects predominantly proximal muscles_**_._

Answer 215

Multiple segmental and radicular arteries, which arise from intercostal and iliac arteries, these originating from the aorta and iliac arteries. \*Radicular arteries: The **posterior** and **anterior radicular arteries** run along the posterior and anterior roots of the spinal nerves and supply them with blood.

Answer 216

Both ASA and PSA originate from vertebral arteries Receive contributions from multiple segmental and radicular arteries (supply nerve roots), which arise from intercostal and iliac arteries, these originating from the aorta and iliac arteries. The largest radicular artery is the artery of Adamkiewicz, which supplies the lower thoracic and upper lumbar regions of the spinal cord (T8 to L3). T4-T8 is a watershed region because: * Cervical and upper thoracic regions receive multiple collaterals from the vertebral arteries and other cervical vessels. Similarly, the conus medullaris and cauda equina are also richly vascularized from the contribution of multiple radicular arteries.

Answer 217

There are anterior and posterior venous systems which drain into radicular veins and eventually into the epidural venous plexus system. _This epidural venous plexus is a valveless system and extends from the pelvic region to the intracranial venous system. This could explain metastatic lesions in the CNS originating from the pelvic region._

Answer 218

_The most common initial symptom is back pain, followed by development of a myelopathic syndrome as the hematoma compresses the cord. It is more common in males, and more frequent in the thoracolumbar region._ _Major risk factors for spinal epidural hematoma include anticoagulation either from medications or from coagulopathies, and thrombocytopenia._ Other factors that may increase the risk of this condition are trauma, neoplasms, pregnancy, and vascular malformations.

Answer 219

Dural arteriovenous fistula is the most common vascular malformation of the spinal cord, and presents with an insidious and slowly progressive myelopathic syndrome, sometimes with acute exacerbations. These manifestations are caused by increased venous congestion and mass effect in the spinal cord, leading to venous infarcts. Acute hemorrhages may occur, however dural arteriovenous fistulas rarely produce epidural hematomas. _The MRI of the spine may show cord signal abnormalities and flow voids, but the definitive diagnostic procedure is conventional angiography._

Answer 220

The majority of ALS cases are sporadic; approximately 10% are familial. Usually autosomal dominant in inheritance, although autosomal recessive forms occur and X-linked inheritance is rare. Mutations in the copper/zinc superoxide dismutase (SOD1) gene on chromosome 21 account for approximately 20% of cases of familial ALS and less than 5% of sporadic ALS cases. The abnormal SOD1 protein usually maintains its dismutase function but appears to damage motor neurons through other mechanisms, including a toxic gain of function of the mutant protein. A rare form of ALS associated with parkinsonism and frontotemporal dementia was identified in a geographically restricted area in the Western Pacific island of Guam.

Answer 221

Neck stiffness and pain, weakness at and below the compression level, and unsteady gait. The examination shows findings of upper motor neuron signs below the level of compression, with spastic paraparesis, hyperreflexia, and upgoing toes. In the upper extremities there may be evidence of lower motor neuron signs such as areflexia and atrophy, mainly at the same level of the compression. Patients have sensory deficits and may experience L’hermitte’s phenomenon, an electric sensation radiating down the back that occurs following neck flexion. The diagnostic test of choice is MRI of the spine. Goals of treatment include prevention of further neurologic deficits and therapies to help improve existing ones. Surgical decompression is the treatment of choice. Nonoperative options may provide pain relief, however once myelopathic findings are evident, this therapeutic option may not alter the course of the disease.

Answer 222

There are two types of radiation-induced myelopathy, a transient and a delayed form. * The transient form happens early, approximately 3 to 6 months after the radiation treatment, and presents with dysesthesias in the extremities which eventually resolve without sequelae. * The delayed form occurs 6 months or greater following radiation therapy, as in this case. The presentation is insidious with paresthesias and dysesthesias of the feet, Lhermitte’s phenomenon, and progressive weakness of the legs. Eventually, bowel and bladder can be affected. The MRI shows increased T2 signal in the affected regions, sometimes with heterogeneous gadolinium enhancement. Steroids have been tried, however, the key is prevention by minimizing the dose of radiation used.

Answer 223

A neurotoxic disorder presenting as a myelopathy with subacute spastic paraparesis. It is endemic in certain parts of Ethiopia, India, and Bangladesh, and occurs from the consumption of Lathyrus sativus, a legume (grass pea or chick pea) which contains the toxin beta-N-oxalylamino-L-alanine. It is more prevalent in poor populations.

Answer 224

A type of myelopathy that presents with a spastic paraparesis of abrupt onset, sometimes associated with involvement of the visual pathways. It is most commonly seen in certain parts of Africa and results from consumption of poorly processed cassava which contains cyanide. It is more prevalent in droughts and in poor populations.

Answer 225

A condition in which there is hypertrophy of extramedullary adipose tissue in the epidural space, and is usually associated with chronic use of steroids. _Patients present with back pain and myelopathic findings. The treatment involves stopping steroids, and sometimes even surgical decompression. MRI of the spine demonstrates the fatty tissue within the spinal canal producing spinal stenosis, which was not described in this patient._

Answer 226

A condition in which there is hypertrophy of extramedullary adipose tissue in the epidural space, and is usually associated with chronic use of steroids. Patients present with back pain and myelopathic findings. The treatment involves stopping steroids, and sometimes even surgical decompression. MRI of the spine demonstrates the fatty tissue within the spinal canal producing spinal stenosis, which was not described in this patient.

Answer 227

_Methylcobalamin (B12) acts as a cofactor for methionine synthase in the reaction where homocysteine is converted to methionine. This enzyme also requires folate as a cosubstrate._ This metabolic pathway is important for DNA synthesis, and when there is lack of the cofactors or substrates, there is dysfunction leading to the clinical manifestations including myelopathy and hematologic disturbances. Folate deficiency can lead to neurologic disturbances like those seen in vitamin B12 deficiency, however, they are less frequent and less severe. When patients have vitamin B12 and folate deficiency, and only folate is supplemented, hematologic abnormalities improve but not the neurologic manifestations. Therefore, both should be supplemented at the same time. In this case folate levels are low, but vitamin B12 levels are within the normal range. However serum vitamin B12 levels can be normal in some patients with vitamin B12 deficiency, and serum methylmalonic acid and total homocysteine levels should be checked since they are more sensitive in detection of these deficiencies. **In folate deficiency, homocysteine levels are elevated and MMA levels are normal.** **In vitamin B12 deficiency, both homocysteine levels and MMA levels are elevated**.

Answer 228

Zinc induces the synthesis of metallothionein in enterocytes. Since copper has a high affinity to the metallothionein, they both enter enterocytes which eventually are sloughed off in the mucosa, leading to loss of copper. Therefore, zinc ingestion may be associated with copper deficiency, and may decrease copper levels.

Answer 229

WNV is a flavivirus transmitted by mosquitoes. It causes an illness characterized by meningitis, encephalitis, and myeloradiculitis. Cases in the USA present during summer months, and the initial symptom is fever, progressing to altered mental status, GI, symptoms, back pain, and flaccid weakness with areflexia, more often proximal and asymmetric and sometimes affecting four limbs. The progression to nadir occurs in 3 to 8 days. Dx w/serology, CSF studies, and PCR. CSF w/neutrophilic pleocytosis with high protein and normal glucose. The MRI shows cauda equina, spinal cord, and/or leptomeningeal enhancement. Pathologic studies have shown perivascular inflammation with anterior horn cell loss in the spinal cord. Vs. Polio virus: poliovirus does not commonly cause the encephalopathic changes seen in WNV, and furthermore it has been eradicated from the United States.

Answer 230

_This is a peroxisomal disorder transmitted in an X-linked fashion and associated with a mutation in the ABCD1 gene on chromosome Xq28 which encodes a peroxisomal adenosine triphosphate-binding cassette transporter protein. Because of this mutation there is an impaired ability to oxidize very long chain fatty acids (VLCFA), especially hexacosanoic acid, leading to the accumulation of very long chain fatty acids in tissues and plasma._ In adrenoleukodystrophy there are four main phenotypes; an early onset cerebral white matter disease (adrenoleukodystrophy), adrenomyeloneuropathy, isolated Addison’s disease, or asymptomatic. In adrenomyeloneuropathy male patients begin having manifestations around age 20, with slowly progressive paraparesis, sensory neuropathy, problems with sphincter control, mild hypogonadism, and mild cognitive impairment. Some patients may develop hearing and visual impairment as well. Most patients also develop adrenal insufficiency. Increased levels of VLCFA in plasma and cultured fibroblasts help in the diagnosis. Patients require steroids for the adrenal insufficiency, however, this medication does not have an effect on the CNS involvement. Very early bone marrow transplantation may be a therapeutic option

Answer 231

This is a peroxisomal disorder transmitted in an X-linked fashion and associated with a mutation in the ABCD1 gene on chromosome Xq28 which encodes a peroxisomal adenosine triphosphate-binding cassette transporter protein. Because of this mutation there is an impaired ability to oxidize very long chain fatty acids (VLCFA), especially hexacosanoic acid, leading to the accumulation of very long chain fatty acids in tissues and plasma. In adrenoleukodystrophy there are four main phenotypes; an early onset cerebral white matter disease (adrenoleukodystrophy), adrenomyeloneuropathy, isolated Addison’s disease, or asymptomatic. In adrenomyeloneuropathy male patients begin having manifestations around age 20, with slowly progressive paraparesis, sensory neuropathy, problems with sphincter control, mild hypogonadism, and mild cognitive impairment. Some patients may develop hearing and visual impairment as well. Most patients also develop adrenal insufficiency. Increased levels of VLCFA in plasma and cultured fibroblasts help in the diagnosis. Patients require steroids for the adrenal insufficiency, however, this medication does not have an effect on the CNS involvement. Very early bone marrow transplantation may be a therapeutic option

Answer 232

Primary or metastatic according to the etiology. Also they can be divided anatomically into extradural, intradural extramedullary, and intradural intramedullary. Primary neoplasms accounting for intramedullary spinal cord metastases include small cell lung cancer, breast cancer, renal cell cancer, lymphoma, and melanoma (MC breast, prostate, lung, renal). However, metastatic intramedullary disease is not very common, and primary intramedullary tumors are more frequent. Most frequent intramural intramedullary tumors: ependymoma (most common spinal cord tumor in adults, from central canal and expand outward) and astrocytomas (most common in children and are slow-growing, low-grade tumor). \*Myxopapillary ependymoma is a type of ependymoma which arises from the ependymal cells in the filum terminale, and is the most common tumor in this location.

Answer 233

Seen in patients with spinal cord lesions above T1, where the spinal sympathetic tract synapses before exiting the spinal cord.

Answer 234

The level of the nipple line correlates with T4. Other levels that are useful landmarks are the base of the neck (C4), the umbilicus (T10), the groin (L1), and the anal region (S5).

Answer 235

The ligaments between the atlas and the axis, as well as the odontoid process are important in maintaining the stability of this articulation. When this articulation fails, or the odontoid is absent or damaged, atlantoaxial dislocation can occur, leading to neck pain, and other manifestations of spinal cord compression including quadriplegia and death. * Rheumatoid arthritis : destructive inflammatory process of the ligaments attaching the odontoid process to the atlas and the skull → atlantoaxial dislocation. * Klippel–Feil syndrome is a decreased number and abnormal fusion of cervical vertebrae. * Morquio syndrome is a skeletal disease in which the odontoid process may be aplastic or absent, leading to secondary spinal cord disease. * Also Down's syndrome

Answer 236

Metastatic disease to the spine most commonly originates from breast, lung, prostate, and kidney cancer, although it is not limited to these. Other invading neoplastic lesions include lymphoma and multiple myeloma. Present w/pain, focal neurologic s(x)s 2/2 from spinal cord compression or dysfunction. The diagnostic test of choice to determine the presence of neoplastic disease is MRI of the spinal cord with gadolinium. _Tx: 1) Steroids - typically dexamethasone (solumedrol 30 mg/kg bolus than 5.4 mg/kg infusion for 23 hours is used for spinal cord traumatic injury), 2) Radiation therapy - or radiosensitive neoplasia: lymphoproliferative disease and germ cell tumors, and for various metastases, particularly in the setting of cord compression. It may be used as a palliative measure to improve symptoms of pain and other symptoms of cord compression. 3) Surgical resection should be entertained when feasible, even in cases of metastatic disease, where it has shown superiority when combined with radiotherapy as compared to radiotherapy alone. However surgical treatments may not be possible in some neoplasms such as in intramedullary lesions._

Answer 237

An initial phase of spinal shock followed by a second phase of increased reflex activity with spasticity The acute spinal shock phase occurs soon after the injury, and lasts for a few weeks (between 1 and 6, but with no exact limits). It is manifested by suppression of spinal segmental activity below the level of the lesion. With complete spinal cord injury, the patient will have a flaccid weakness with areflexia below the lesion, atonic bladder with overflow incontinence, distention of the bowel with absence of peristalsis and constipation, depressed rectal tone and abolished genital reflexes. There is autonomic dysfunction below the lesion explaining the hypotension seen in these cases. A few weeks after the spinal cord injury, the patient will start presenting features of increased reflexic activity below the lesion. In this second stage there are upper motor neuron findings with increased tone leading to spasticity and hyperreflexia. Plantar responses are upgoing, triple flexion response commonly occurs. _Patients will have detrusor spasms and hyperactivity with urinary loss secondary to spontaneous bladder contraction as well as spontaneous reflex defecation. These bladder and bowel reflexes are probably explained by the lack of inhibition of the sacral neurons by rostral centers, leading to spontaneous contraction secondary to a local reflex arc._

Answer 238

From hemosiderin deposits in the subpial layers of the brain and spinal cord, which is secondary to recurrent bleeding into the subarachnoid space. The bleeding source is undetermined in most cases. Some risk factors identified - previous subarachnoid hemorrhage, head trauma, and previous intradural surgery, however the significance of these historical aspects is not clear. The most common manifestations include gait ataxia and sensorineural hearing loss. Other clinical manifestations include anosmia, cognitive decline, and myelopathic findings. Xanthochromia and/or the presence of red blood cells is a common CSF finding. MRI shows T2-weighted hypointensity around the brain, brainstem and spinal cord, and sometimes intraspinal fluid collections are detected. No clear tx - if source of bleeding is found, can consider surgical intervention but no clear data showing that this affects outcome

Answer 239

Tabes dorsalis, spinal cord infarction from vasculitis or meningovascular syphilis, meningomyelitis manifested as an inflammatory myelitis, and more unusual and uncommon forms such as hypertrophic pachymeningitis and gummas, which can be intramedullary or extramedullary.

Answer 240

Characterized by dysfunction of the posterior columns with prominent sensory ataxia and proprioceptive loss, along with other manifestations such as sphincter dysfunction, Lhermitte’s sign, lancinating pain, and areflexia. The natural history of tabes dorsalis has been described in three different phases: 1. A preataxic phase in which the patient has lancinating pain of his legs, along with sphincter and sexual dysfunction. 2. The ataxic phase with prominent proprioceptive loss, sensory ataxia leading to the development of Charcot joints. 3. A postataxic or paralytic phase characterized by spastic paraparesis, autonomic dysfunction, worsening of the pain and sphincter dysfunction, and cachexia. Pathologic findings demonstrate inflammation, demyelination, and gliosis of the posterior columns and dorsal roots of the spinal cord.

Answer 241

The treatment of neurosyphilis is Penicillin G intravenously, with a dose of 24 million units daily in divided doses for 14 days.

Answer 242

The treatment of neurosyphilis is Penicillin G intravenously, with a dose of 24 million units daily in divided doses for 14 days.

Answer 243

Conus medullaris: **sensory deficits in a saddle distribution, which is usually bilateral and symmetric. Pain is often symmetric, but is not typically radicular**. There is **usually lower extremity symmetric weakness** and sometimes **decreased or absent ankle reflexes, but this may be mild**. KNEE JERKS PRESERVED. **Bowel and bladder dysfunction** occur **early** in the course of the disease, as well as FREQUENT sexual dysfunction. Cauda equina presents: **distinctive radicular pain with an asymmetric distribution. Motor deficits are also asymmetric with evidence of hyporeflexia, LOSS OF KNEE JERKS.** **Bowel and bladder function** may be affected but usually this occurs **later** in the course and less frequently than with conus lesions. SOMETIMES IMPOTENCE. _Spasticity and other upper motor neuron signs will not be present as this is a lower motor neuron disorder._

Answer 244

Evidence of ongoing denervation indicated by the presence of spontaneous activity (fibrillation potentials) and chronic denervation (reduced recruitment, polyphasic motor units). Other variable features include fasciculation potentials and motor unit instability (variability of amplitude of the motor unit and repetitive discharges). Reduced motor unit recruitment with a rapid firing rate on EMG reflects compensation of existing motor units for those that are no longer functional, and only a single motor unit may be seen to be activated during voluntary contraction in a severely denervated muscle. Sensory NCS are normal. EMG/NCS is indicated in the evaluation of a patient with suspected ALS, and should include evaluation of cervical, thoracic, and lumbosacral regions routinely, and of bulbar region when clinically affected.

Answer 245

Laboratory tests may include evaluation of parathyroid hormone, paraneoplastic autoantibodies (such as anti-Hu), GM1 autoantibodies, and others depending on the suspicion. MRI of the brain and spinal cord are indicated to exclude other potential causes masquerading clinically as ALS such as cervical spondylosis. MRI in ALS may show increased signal in the corticospinal tract on T2-, proton density-, and FLAIR-weighted images, possibly due to wallerian degeneration.

Answer 246

Copper deficiency causes a myelopathy similar to that seen in B12 deficiency. It also produces multiple other neurologic manifestations, including peripheral neuropathy, central nervous system demyelination, myopathy, and optic neuropathy. Hematologic manifestations are also seen in copper deficiency, with anemia, neutropenia, and left shift in granulocytic and erythroid maturation. MRI of the spine may show T2-signal hyperintensity in the paramedian cord, most frequently in the **cervical** level. Copper deficiency results from malabsorption, one of the most common causes being previous gastric surgery, especially bariatric surgery for weight loss. It is frequent to find vitamin B12 deficiency along with copper deficiency, and in most cases inclinical practice, B12 is supplemented while copper is usually overlooked. Lack of improvement with vitamin B12 supplementation should prompt evaluation for copper deficiency. Excessive zinc ingestion may also contribute to copper deficiency, since zinc induces the synthesis of metallothionein in enterocytes, which has a high affinity to copper, leading to internalization of copper into the enterocytes and its eventual loss when they are sloughed off in the mucosa.

Answer 247

Copper deficiency causes a myelopathy similar to that seen in B12 deficiency. It also produces multiple other neurologic manifestations, including peripheral neuropathy, central nervous system demyelination, myopathy, and optic neuropathy. Hematologic manifestations are also seen in copper deficiency, with anemia, neutropenia, and left shift in granulocytic and erythroid maturation. MRI of the spine may show T2-signal hyperintensity in the paramedian cord, most frequently in the **cervical** level. Copper deficiency results from malabsorption, one of the most common causes being previous gastric surgery, especially bariatric surgery for weight loss. It is frequent to find vitamin B12 deficiency along with copper deficiency, and in most cases inclinical practice, B12 is supplemented while copper is usually overlooked. Lack of improvement with vitamin B12 supplementation should prompt evaluation for copper deficiency. Excessive zinc ingestion may also contribute to copper deficiency, since zinc induces the synthesis of metallothionein in enterocytes, which has a high affinity to copper, leading to internalization of copper into the enterocytes and its eventual loss when they are sloughed off in the mucosa.

Answer 248

(X-linked spinobulbar muscular atrophy). Kennedy’s disease typically presents in males beginning the fourth decade of life. The clinical presentation includes motor weakness often starting in proximal muscles associated with features of lower motor neuron dysfunction such as atrophy and hyporeflexia. Tremor, muscle cramps, and fasciculations are other features of this condition. Fasciculations involving the face and perioral region are present in the majority of patients. Later in the course of the disease, evidence of bulbar dysfunction becomes apparent. Examination may reveal gynecomastia, but its absence does not preclude this diagnosis. Endocrine abnormalities, including hypogonadism with sterility and diabetes, occur in some patients. Kennedy’s disease results from expansion of a CAG repeat in the androgen receptor protein gene on the X chromosome. Genetic testing for this disorder is commercially available. Treatment is supportive.

Answer 249

The spinal cord lies dorsal to the posterior longitudinal ligament.

Answer 250

The vertebral column is composed of vertebral bodies, pedicles, and laminae. * Two pedicles arise from the posterior aspect of each vertebral body, and then fuse posteriorly through two laminae, leaving the spinal canal in the middle within which the spinal cord lies. * The ligamentum flavum runs in the posterior aspect of the spinal canal, and the denticulate ligament extends on both sides of the spinal cord between the pia mater and the dura mater. * Between each vertebral body there is an intervertebral disc, which is composed of a central nucleus pulposus and a surrounding annulus fibrosus.

Answer 251

The spinal **cord** has 31 segments and a corresponding number of pairs of spinal nerve roots, with 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. The cervical nerve roots exit the spinal column above the vertebral body of the same number, except for C8, which exit between the C7-T1 intervertebral foramen. The subsequent nerve roots below this level will exit the spinal column below the corresponding vertebral body. _In adults, the spinal cord extends from the foramen magnum to the level of L1-L2. It has two major enlargements, one in the cervical region, and another one in the lumbosacral region. These enlargements correlate with the areas related to innervation of the upper and lower extremities._

Answer 252

_Commercially available molecular analysis of the SMN gene is available. Serum creatine kinase may be significantly elevated (more than 10 times normal), particularly in the younger-onset forms._ Sensory NCSs are normal; EMG shows evidence of acute and chronic denervation and reinnervation, with large polyphasic motor units. Complex repetitive discharges occur in SMA type 3. _Muscle biopsy shows atrophy of entire fascicles or groups of fascicles, with normal or hypertrophied neighboring fascicles._

Answer 253

The majority of cases of SMA are due to mutations in the survival motor neuron (SMN) 1 gene on chromosome 5. Inheritance is autosomal recessive in most cases, though a minority of cases involving other genes with autosomal dominant or X-linked inheritance have been identified. The gene product, SMN1 protein, is involved in RNA processing. In later-onset forms, some residual functional protein is present, leading to the milder phenotype.

Answer 254

This patient has nitrous oxide toxicity, causing a neurologic manifestation which has been termed as “anesthesia paresthetica.” Nitrous oxide is an inhalational anesthetic agent which produces irreversible oxidation of cobalamin, and makes the methylcobalamin inactive. The manifestations occur in patients with underlying cobalamin deficiency even after a single exposure to nitrous oxide, usually with a rapid onset of symptoms. However, chronic exposure can lead to similar manifestations, and this has been described among anesthetists, dentists, or medical personnel working with nitrous oxide, either from occupational exposure or from abuse. Patients with chronic exposure can have an acute exacerbation during an acute exposure to larger amounts of nitrous oxide. The neurologic manifestations include myelopathy, neuropathy or even cognitive changes, and encephalopathy. MRI changes with T2 hyperintensity can be detected. Prophylactic vitamin B12 can help prevent this condition.

Answer 255

_This condition presents in young patients of Asian origin, and it is characterized by progressive asymmetric wasting of one or both hands and forearms. Examination shows atrophy and fasciculations with no sensory deficits. These patients have a high incidence of atopic disorders. The pathophysiology is not understood, but some have suggested a chronic progressive compression of the cervical cord, associated with dynamic changes of the cervical dural sac and spinal cord induced by neck flexion. The MRI of the cervical spine in flexion demonstrates cervical cord thinning with signal changes. A cervical collar may be used to prevent neck flexion, and surgical intervention may have an impact in some patients._ _LMN findings of the BUE_

Answer 256

Risk factors include _diabetes mellitus, intravenous drug use, previous infection, history of spine injury or spine surgery, renal disease, and multiple medical comorbiditie_s. The most common presenting symptoms are fever, low back pain, and progressive neurologic symptoms attributed to cord or root compression. Myelopathic findings develop over time, and patients may have upper motor neuron findings below the level of the lesion. Sometimes the patient worsens rapidly and examination may show findings of spinal shock. The symptoms may ascend over time as the epidural abscess propagates cranially. MRI of the spine is the standard test for diagnosis and is very sensitive. _A lumbar puncture is not usually performed, and may be contraindicated due to risk of spread of infection to the intrathecal compartment. Furthermore, CSF cultures are only positive in 25% of cases._ _The most common organism is Staphylococcus aureus, followed by Streptococci, gram-negative bacilli, and anaerobic organisms._ Empiric broad spectrum antibiotics should be started early, with narrowing of the spectrum once a specific organism is identified. _The usual duration of antibiotic therapy is between 4 and 6 weeks, however, antibiotics alone may not be effective._ Once this condition is suspected, an urgent neurosurgical consultation should be obtained. If the patient has findings of cord compression, surgical evacuation should be performed. Epidural spinal abscess is a true neurosurgical and neurologic emergency.

Answer 257

Spinal muscular atrophy

Answer 258

PMA, SMA, benign focal amyotrophy

Answer 259

B12 deficiency

Answer 260

Cu (also B12) deficiency

Answer 261

One anterior spinal artery

Answer 262

The artery of Adamkiewicz typically arises from the left side of the aorta between T8 and L2 (usually T9 to T12, although the artery of Adamkiewicz is found above T8 in about 15% of people), and has been documented as having a diameter anywhere from 0.6 to 1.8 mm.

Answer 263

Two posterior spinal arteries

Answer 264

Anesthesia parasthetica

Answer 265

Vacuolar myelopathy

Answer 266

Artery of Adamkiewicz

Answer 267

Brown-Sequard syndrome

Answer 268

Tabes dorsalis

Answer 269

ABCD1 gene on Xq28

Answer 270

ABCD1 gene on Xq28

Answer 271

Epidural lipomatosis

Answer 272

CIDP usually presents in adult patients between 40 and 60 years of age, and it is progressive and/or relapsing, with a time course of at least 8 weeks necessary for the diagnosis to be made. When the clinical symptoms do not progress beyond 4 weeks, GBS is the likely diagnosis. When symptoms relapse after treatment and/or symptom progression extends beyond 4 weeks (but \<8 weeks), the diagnosis is controversial. Some authors suggest the term subacute inflammatory demyelinating polyradiculoneuropathy to describe patients in this time frame, with manifestations similar to both acute inflammatory demyelinating polyneuropathy and CIDP. CIDP is the diagnosis when symptoms progress or relapse beyond 8 weeks.

Answer 273

Sural nerve biopsy should be considered when the CSF or electrophysiologic studies are not supportive of the diagnosis. In CIDP the biopsy will typically show evidence of demyelination and remyelination with onion-bulb formation, and sometimes evidence of inflammation. Nerve biopsy may be helpful to exclude other conditions.

Answer 274

May occur in CIDP but more common in GBS

Answer 275

Carpal tunnel syndrome may be unilateral or bilateral. Symptoms of carpal tunnel include pain and paresthesias in the lateral (radial) half of the palm and first three digits and lateral half of the fourth digit, that classically awaken the patient at night, with patients shaking their hand to relieve symptoms. Shooting pains may radiate up the forearm or even the upper arm; therefore, presence of forearm or upper arm symptoms should not exclude the diagnosis of carpal tunnel syndrome. Sensation is spared over the thenar eminence because the palmar sensory branch that innervates the thenar eminence travels outside the carpal tunnel. Physical examination may show provocation of symptoms with repetitive tapping on the median nerve at the wrist (Tinel’s sign) and with hyperflexion of the wrists for a period of time (Phalen’s maneuver). T_he only motor branch of the median nerve distal to the carpal tunnel is the thenar (or recurrent) motor branch; in advanced carpal tunnel, the thenar muscles are therefore weak and atrophied and show evidence of denervation on EMG. In such cases, there is weakness of thumb abduction and opposition, with weakness in activities requiring fine motor coordination of the first three digits such as buttoning._

Answer 276

A rare autosomal recessive disorder that manifests in early childhood. It affects intermediate filaments of both the central and peripheral nervous system, leading to a predominantly axonal sensorimotor neuropathy, corticospinal tract involvement with upper motor neuron signs, and optic atrophy leading to vision loss. * The characteristic gait includes walking on the inner edges of the feet. * The integument is also involved, and patients often have tightly curled hair. Neuropathologic analysis of nerves from patients with this disorder reveals pathognomonic findings of large focal axonal swelling that contain tightly packed disorganized neurofilaments. This disorder is due to mutations in the GAN gene that encodes for gigaxonin, which is involved in cross linking of intermediate filaments. It is progressive and death typically occurs by adolescence.

Answer 277

A rare autosomal recessive disorder that manifests in early childhood. It affects intermediate filaments of both the central and peripheral nervous system, leading to a predominantly axonal sensorimotor neuropathy, corticospinal tract involvement with upper motor neuron signs, and optic atrophy leading to vision loss. * The characteristic gait includes walking on the inner edges of the feet. * The integument is also involved, and patients often have tightly curled hair. Neuropathologic analysis of nerves from patients with this disorder reveals pathognomonic findings of large focal axonal swelling that contain tightly packed disorganized neurofilaments. This disorder is due to mutations in the GAN gene that encodes for gigaxonin, which is involved in cross linking of intermediate filaments. It is progressive and death typically occurs by adolescence.

Answer 278

RD is an autosomal recessive (Ching-Ching says dominant, weird) peroxisomal disorder that results from a defect in an enzyme involved in fatty acid metabolism, leading to accumulation of an intermediate in this pathway, phytanic acid. Clinical manifestations include retinitis pigmentosa (with night blindness and visual field constriction), cardiomyopathy, and skin changes. Neurologic manifestations include neuropathy, hearing loss, anosmia, ataxia, and cerebellar signs. The neuropathy is a large- fiber sensorimotor neuropathy. The presence of overriding toes due to a shortened fourth metatarsal may aid in the diagnosis. Treatment includes dietary modification to reduce dietary intake of phytanic acid.

Answer 279

In myoneurogastrointestinal encephalopathy (MNGIE), intestinal pseudoobstruction is a prominent feature; other features include ophthalmoparesis and a demyelinating neuropathy. MNGIE is due to a mutation in the thymidine phosphorylase gene.

Answer 280

In myoneurogastrointestinal encephalopathy (MNGIE), intestinal pseudoobstruction is a prominent feature; other features include ophthalmoparesis and a demyelinating neuropathy. MNGIE is due to a mutation in the thymidine phosphorylase gene.

Answer 281

Abetalipoproteinemia, also known as Bassen–Kornzweig syndrome, is an autosomal recessive disorder that results in defective triglyceride transport, leading to abnormal very low- density lipoprotein secretion. Fat malabsorption results in deficiencies in vitamins A, E, D, and K. Low levels of serum β- lipoprotein and vitamin E in the serum suggest the diagnosis. Peripheral smear shows acanthocytes. Clinical manifestations include retinitis pigmentosa, neuropathy, and ataxia.

Answer 282

Acute inflammatory demyelinating polyradiculoneuropathy, common cause of ascending paralysis. It affects any age group and any gender in all parts of the world. In about 60% of cases, there is a preceding respiratory or gastrointestinal illness 1 to 3 weeks prior. Campylobacter jejuni is an identifiable etiology of the preceding gastrointestinal illness in some cases and is associated predominantly with the axonal variant. GBS is considered to be caused by an immunologic reaction to the peripheral nerves. The main mechanism is a T-cell–mediated response against myelin proteins that occurs after encountering a cross-reactive antigen, leading to the release of cytokines and activation of macrophages that will damage peripheral myelin. During the process, there is mononuclear infiltration into the peripheral nerves, T-lymphocyte activation, and antibody binding to Schwann cells and myelin components, with macrophages targeting the myelin components. Axonal variants of GBS exist, and are less responsive to treatment with protracted course and worse prognosis. The typical clinical presentation begins with sensory symptoms, especially paresthesias beginning distally, usually in the toes and feet, ascending through the lower extremities, and later the upper extremities. Some patients complain of burning pain, with cramps or muscle discomfort. Lower extremity weakness begins later, and is usually symmetric and ascending from distal to proximal, evolving over days. There is subsequent involvement of the hands and upper limbs, and weakness of the respiratory and bulbar muscles may occur later. Reduced or absent reflexes are evident on examination. Involvement of the autonomic nervous system and respiratory muscles may occur in patients with GBS, and there may be rapid progression with life-threatening complications, such as arrhythmias, bradycardia, tachycardia, hemodynamic instability, and respiratory failure. A patient who is rapidly worsening should be observed with cardiac monitoring and frequent vital sign assessment, as well as frequent evaluation of respiratory parameters, including negative inspiratory force and vital capacity. A negative inspiratory force of less than −30 cc H2O or vital capacity of less than 15 to 20 mL/kg support elective endotracheal intubation.

Answer 283

Familial amyloid polyneuropathy: group of AD 2/2 deposition amyloid protein in peripheral neves, heart, kidney. etc FAP1 - polyneuropathy, autonomic features, a family history (3rd, 4th decade of life, with involvement o both small and large fibers but more pronounced loss of pain and temperature) FAP2 - CTS, family history CTS, mild predominantly sensory polyneuropathy, and absence of autonomic features (manifests later than FAP1 in 4th and fifth decade) For above 2: Nerve, rectal, or fat pad biopsy with congo red staining demonstrates amyloid, which exhibits an apple-green birefringence on polarized light; transthyretin molecular gene testing is also available for diagnosis. Liver transplant may be helpful for FAPs resulting from transthyretin mutations. FAP3/FAP4 - rare, not related to abnormalities in transthyretin FAP3 - similar clinically to FAP1 but with earlier renal involvement and more GI involvement (others include hypothyroidism, adrenal insufficiency, and sexual dysfunction), 2/2 abnormalities in apolipoprotien A1 FAP4 - 3rd decade of life with corneal dystrophy being an early feature, later life with CN: VII, VIII, XII and skin changes, 2/2 abnormalities in gelsolin

Answer 284

Familial amyloid polyneuropathy: group of AD 2/2 deposition amyloid protein in peripheral neves, heart, kidney. etc FAP1 - polyneuropathy, autonomic features, a family history (3rd, 4th decade of life, with involvement o both small and large fibers but more pronounced loss of pain and temperature) FAP2 - CTS, family history CTS, mild predominantly sensory polyneuropathy, and absence of autonomic features (manifests later than FAP1 in 4th and fifth decade) For above 2: Nerve, rectal, or fat pad biopsy with congo red staining demonstrates amyloid, which exhibits an apple-green birefringence on polarized light; transthyretin molecular gene testing is also available for diagnosis. Liver transplant may be helpful for FAPs resulting from transthyretin mutations. FAP3/FAP4 - rare, not related to abnormalities in transthyretin FAP3 - similar clinically to FAP1 but with earlier renal involvement and more GI involvement (others include hypothyroidism, adrenal insufficiency, and sexual dysfunction), 2/2 abnormalities in apolipoprotien A1 FAP4 - 3rd decade of life with corneal dystrophy being an early feature, later life with CN: VII, VIII, XII and skin changes, 2/2 abnormalities in gelsolin

Answer 285

Can involve multiple organ systems. In the cardiovascular system, manifestations include resting tachycardia or bradycardia, loss of the respiratory variability of the heart rate, loss of the normal tachycardic response, orthostatic hypotension, and increased risk of silent myocardial infarction. Gastrointestinal abnormalities may occur, ranging from delayed gastric emptying, constipation from colonic atony, bacterial overgrowth, and diarrhea, which is typically nocturnal. Neurogenic bladder may occur, as well as sexual dysfunction caused by impotence, erectile dysfunction, and retrograde ejaculation. Abnormalities in sudomotor function also occur, with areas of hypohidrosis and hyperhidrosis.

Answer 286

CMTs: AKA hereditary sensorimotor neuropathies or peroneal muscular atrophy, are a large, heterogeneous group of inherited peripheral neuropathies. The CMTs can be divided into demyelinating, axonal, and combined demyelinating and axonal forms. They are genetically heterogeneous. Demyelinating CMTs: CMT1, CMTX * NCS generally show diffuse, uniformly slow conduction velocities without conduction blocks or temporal dispersion, indicating a hereditary as opposed to acquired demyelinating process, can have secondary axonal loss with loss of amplitude, increase in distal latency, and decrease in CV * CMT1 - multiple types, AD inheritance, CMT1A MC type, clinical manifestations typically begin in the first two decades of life and include slowly progressive weakness, muscle atrophy, kyphosis, and mild (often asymptomatic) sensory loss. Other signs include hammertoes, high-arched feet, palpably enlarged nerves due to peripheral nerve hypertrophy (which more commonly occurs in the CMT1 group compared to the other CMTs), and pes cavus. Involvement of the upper extremities typically occurs later in life. Usually there is family hx but can be difficult to elucidate because of variable expression. CMT1A gene implicated is duplication n PMP22 gene on chasm 17 (CMT1B more severe, myelin protein 0 gene). On nerve biopsy, pathologic features of the demyelinating inherited polyneuropathies include demyelination and an onion- bulb appearance due to Schwann cell proliferation. Onion bulbs are not specific for CMT, and also occur with chronic inflammatory demyelinating polyneuropathy (discussed in questions 11, 12, and 38). * CMTX is the second most common type of CMT. It is demyelinating and is clinically similar to CMT1, but it is X-linked in inheritance; males therefore tend to be more severely affected compared to females. It is due to a mutation in the connexin 32 gene. * CMT3, also known as Dejerine–Sottas syndrome or hypertrophic neuropathy of infancy, is one of the more severe forms of the demyelinating CMTs. It presents in infancy with proximal weakness, absent deep tendon reflexes, and hypertrophy of the peripheral nerves. Prominent sensory symptoms including pain and dysesthesias occur. Patients typically have extensive disability early in life. Both autosomal recessive and dominant forms exist. CSF protein is usually elevated. Congenital hypomyelination is seen along the spectrum of this disorder. CMT3 is genetically heterogeneous; mutations in several genes including PMP22, protein myelin 0, and other genes implicated in defective demyelination are associated with CMT3. Combined: CMT4, clinical features of subtypes include vision loss, severe scoliosis, and hearing loss Axonal: CMT2 with lateral symptoms and less severe foot/spine deformities, CMT2A with optic atrophy, CMT2B with foot ulcerations, CMT2C with vocal cord, intercostal, and diaphragmatic weakness, CMT2D hand involved more than feet, genes implicated related to axonal transport and membrane trafficking, CMT2A2 is MC of this group and due to mutations in mitofusin 2.

Answer 287

Plasmapheresis is used in four to six treatments of 200 to 250 mL/kg. There is also evidence to support the use of IVIG, and its use has shown similar efficacy to plasmapheresis. Its dose is 400 mg/kg/day for 5 days. The combination of plasmapheresis and IVIG has failed to show additional improvement when compared to either therapy alone. The use of steroids is not beneficial and not recommended. Pyridostigmine is used for symptomatic treatment of myasthenia gravis (discussed in Chapter 10), and not for GBS.

Answer 288

Plasmapheresis is used in four to six treatments of 200 to 250 mL/kg. There is also evidence to support the use of IVIG, and its use has shown similar efficacy to plasmapheresis. Its dose is 400 mg/kg/day for 5 days. The combination of plasmapheresis and IVIG has failed to show additional improvement when compared to either therapy alone. The use of steroids is not beneficial and not recommended. Pyridostigmine is used for symptomatic treatment of myasthenia gravis (discussed in Chapter 10), and not for GBS.

Answer 289

It is an autosomal dominant predominantly demyelinating hereditary neuropathy with incomplete penetrance and is caused by a deletion in the peripheral myelin protein 22 gene (PMP22). Duplications in this same gene are the cause of Charcot–Marie–Tooth type (CMT) 1A. Patients with HNPPs classically present with recurrent episodes of focal mononeuropathies or plexopathies of the upper or lower limbs; the peroneal nerve is most commonly affected, followed by the ulnar nerve. The presentation is typically in young adulthood, and a history of compression or traction on the involved nerve can often be elicited. The weakness is not preceded or accompanied by pain, distinguishing HNPP from hereditary neuralgic amyotrophy (Parsonage–Turner), which can also lead to recurrent upper extremity mononeuropathies. Other phenotypes of HNPP, including one resembling CMT or a chronic sensorimotor demyelinating polyneuropathy resembling chronic inflammatory demyelinating polyneuropathy, also exist. NCS show prolonged distal latencies, focal slowing at sites of compression, and in some cases diffuse reductions in SNAP amplitudes. Nerve biopsy shows a characteristic pattern of focal, sausage-like areas of thickening in the myelin called **tomacula**, as well as evidence of segmental demyelination and axon loss. Nerve biopsy does not typically show significant inflammation in this disorder.

Answer 290

Diabetic neuropathy has significant clinical implications. Patients with polyneuropathy are at risk for developing foot ulcers and ankle arthropathy (discussed also in Chapter 16). Foot ulcers are a severe complication caused by a combination of factors, including loss of sensation from neuropathy leading to unnoticed trauma, poor vascular perfusion, and higher risk of infection. Ankle arthropathy, known as “Charcot joint,” is a joint deformity associated with loss of sensation and sensory ataxia resulting from neuropathy. Mononeuropathies can involve peripheral or cranial nerves. A typical cranial nerve affected by diabetes is the third nerve, which can occur acutely, usually sparing the pupillary function (discussed

Answer 291

The patient has a history and examination consistent with acute brachial plexitis, also known as _neuralgic amyotrophy_ or Parsonage–Turner syndrome. This can occur following surgery, vaccination, or systemic viral illness; in some cases, it can be idiopathic. Symptoms of acute brachial neuritis include acute onset of severe shoulder and arm pain, which then resolve, with subsequent occurrence of weakness. This disorder can potentially affect any portion of the brachial plexus and frequently affects multiple nerves originating from the brachial plexus in a multifocal fashion. It can, however, be isolated to a single upper extremity nerve. Nerves frequently affected include the suprascapular nerve, long thoracic nerve, and median nerve. It can also occur in the lumbosacral plexus. This disorder is most often monophasic with good recovery, but recurrent episodes may occur. _There is a familial form, hereditary neuralgic amyotrophy, which is autosomal dominant in inheritance. Recovery typically occurs after each attack, though with time residual deficits may be incurred. Some cases of hereditary neuralgic amyotrophy have been linked to SEPT9 gene on chromosome 17_.

Answer 292

Radiation-induced plexopathy can occur months to years following exposure to radiation. _Unlike carcinomatous invasion, radiation-induced plexopathy is painless. Myokymia on EMG further supports the diagnosis and distinguishes it from carcinomatous invasion_.

Answer 293

Radiation-induced plexopathy can occur months to years following exposure to radiation. _Unlike carcinomatous invasion, radiation-induced plexopathy is painless. Myokymia on EMG further supports the diagnosis and distinguishes it from carcinomatous invasion_.

Answer 294

This patient has Miller Fisher syndrome, which is associated with the presence of the antibody GQ1b. Miller Fisher syndrome, described by C. Miller Fisher, is a variant of Guillain–Barre syndrome (GBS), characterized by the triad of ataxia, ophthalmoplegia, and areflexia. _Antibodies to GQ1b are present in 90% of patients with Miller Fisher syndrome. Antibodies to GQ1b can also lead to isolated ocular nerve abnormalitie_

Answer 295

This patient has Miller Fisher syndrome, which is associated with the presence of the antibody GQ1b. Miller Fisher syndrome, described by C. Miller Fisher, is a variant of Guillain–Barre syndrome (GBS), characterized by the triad of ataxia, ophthalmoplegia, and areflexia. Antibodies to GQ1b are present in 90% of patients with Miller Fisher syndrome. Antibodies to GQ1b can also lead to isolated ocular nerve abnormalitie

Answer 296

Genetically and phenotypically heterogeneous group of hereditary neuropathies. As a group, they share in common prominent sensory signs and symptoms, including pain, sensory loss, and autonomic features with little motor involvement. Because of the sensory loss, patients with HSANs are prone to painful calluses, stress fractures, neuropathic (Charcot) joints, skin ulcerations that heal poorly, and infections with deep tissue involvement, such as osteomyelitis, leading to disfiguring acral mutilations. HSAN1 is the most common HSAN. It is autosomal dominant. Presentation is typically in young adulthood. Painful sensory symptoms such as lancinating pains are prominent. There is relatively dissociated sensory loss, with pain and temperature affected more than dorsal column modalities. The main autonomic manifestation is hypohidrosis. Only in advanced cases do muscle weakness and atrophy occur. Hearing loss can rarely occur. HSAN1 results from a mutation in the gene encoding for serine palmitoyltransferase, which catalyzes the rate-limiting step of sphingolipid synthesis. HSAN2 begins in infancy, and is characterized by generalized loss of sensation and insensitivity to pain, leading to significant risk of mutilation to the hands, feet, lips, and tongue. Autonomic symptoms are not prominent and cognitive function is normal. Associated features include areflexia and retinitis pigmentosa. NCS show evidence of axon loss, with absence of SNAPs. HSAN3, also known as familial dysautonomia or Riley–Day syndrome, an autosomal recessive HSAN with prominent autonomic features. Symptom onset is in infancy with dysphagia, vomiting, recurrent infections, and blood pressure lability. It is particularly prevalent among Ashkenazi Jews. With emotional stimulation, there is hyperhidrosis, skin flushing, and hypertension. Other autonomic features include absence of lacrimation. The tongue may be smooth due to absence of fungiform papillae. Later in life, evidence of a predominantly sensory neuropathy with insensitivity to pain occurs, as well as areflexia. Nerve biopsy shows a marked reduction in the density of unmyelinated axons and small myelinated axons, with a reduction in autonomic ganglia cell bodies. HSAN3 is due to a mutation in the IKAP gene, which results in abnormal mRNA splicing, leading to dysregulation of neural endocytosis. HSAN4, or congenital insensitivity to pain. This is an autosomal recessive disorder marked by insensitivity to pain, leading to repeated injury and self-mutilation. Cognitive delay is also present, as are significant behavioral problems including hyperactivity. Autonomic features include anhidrosis, leading to heat intolerance and frequent fevers. There is little evidence of large-fiber sensory or motor neuropathy on examination or EMG/NCS; diagnosis is made by demonstration of absent or a markedly reduced number of unmyelinated axons and small myelinated fibers on skin biopsy, absence of nerve endings in sweat glands, as well as absence of sweating by quantitative sudomotor axon-reflex test. This disorder results from mutations in the tyrosine kinase receptor for nerve growth factor NTRK1, which plays a role in the development of unmyelinated nociceptive and sudomotor fibers. Prominence of sensory features with relatively few motor manifestations and the presence of autonomic signs and symptoms distinguish the HSANs from Charcot–Marie–Tooth (CMT).

Answer 297

This patient has cryoglobulinemia, in which complement levels are reduced. The clinical manifestation of cryoglobulinemia includes nonspecific constitutional symptoms, palpable purpura, arthralgias, lymphadenopathy, hepatosplenomegaly, and peripheral neuropathy, including mononeuritis multiplex. _Cryoglobulins are immunoglobulins that precipitate when exposed to cold temperatures and redissolve on rewarming (discussed also in_ _Chapter 16__)._ CNS involvement may occur in the form of ischemic stroke. This condition is frequently associated with hepatitis C, and sometimes has been found in patients with HIV. Other associated conditions are the monoclonal gammopathies, such as multiple myeloma, and connective tissue diseases. Treatment includes immunosuppressive therapies such as steroids and cyclophosphamide. In some cases, plasmapheresis has shown beneficial results.

Answer 298

This patient’s history is consistent with primary erythromelalgia, a rare autosomal dominant disorder characterized by episodes of severe burning and erythema of the distal extremities. These episodes may be precipitated by exposure to either heat or cold. Patients are typically asymptomatic between episodes. This disorder is due to mutations in the voltage-gated sodium channel SCN9A gene, which results in hyperactivity of the dorsal root ganglia. In the patient presented in question 80, the family history and normal routine laboratory testing make primary erythromelalgia the more likely diagnosis. However, there are secondary causes of erythromelalgia that warrant consideration in the appropriate clinical context. * Secondary erythromelalgia can be seen with polycythemia rubra vera and other myeloproliferative disorders, systemic lupus erythematosus and other autoimmune disorders. Some secondary causes of erythromelalgia respond to aspirin therapy. * Note that Fabry’s disease is on the differential diagnosis of erythromelalgia as Fabry’s can lead to painful acroparesthesias that are worsened with heat exposure and exercise, but evidence of small-fiber neuropathy on examination and other findings on history and examination distinguish between these two disorders (discussed in question 70). There is no evidence of small-fiber neuropathy due to glucose intolerance, and the episodic nature of the symptoms further excludes that diagnosis. The episodic nature of the symptoms with normal examination otherwise is evidence that this is not hereditary sensory and autonomic neuropathy type I.

Answer 299

This patient has a sensory neuronopathy or ganglionopathy, in which the dorsal root ganglia are involved, presenting with progressive sensory deficits that are usually non-length dependent, patchy, and asymmetric, and lead to global sensory loss. Sensory ataxia is a characteristic finding of sensory neuronopathy. Patients are also areflexic; however, strength tends to be normal. Some patients may also have autonomic dysfunction. Pyridoxine intoxication is one of the causes of sensory neuronopathy, and therefore should not be supplemented. There are several other potential etiologies of sensory neuronopathy. It is frequently secondary to a primary pathology, and can be paraneoplastic, especially associated with small cell lung cancer, in which anti-Hu antibodies are typically present. It may be associated with other neoplasms, such as neuroendocrine tumors, lymphomas, breast and ovarian cancers, and sarcomas. Another condition that typically can cause sensory neuronopathy is Sjogren’s syndrome, which is a condition characterized by inflammation of the exocrine glands leading to keratoconjunctivitis sicca and xerostomia (discussed in Chapter 16). The diagnostic work-up includes Schirmer’s test, SSA and SSB antibodies, and lip biopsy to detect inflammatory changes in small salivary glands. Other causes of sensory neuronopathy include HIV infection, HTLV-1, Epstein–Barr virus, varicella zoster virus, measles, monoclonal gammopathies, nicotinic acid deficiency, vitamin E deficiency, riboflavin deficiency, and drugs such as carboplatin, doxorubicin, suramin, thallium, and penicillin. Electrophysiologic studies demonstrate absent or low amplitude SNAPs. Motor nerves are not typically involved.

Answer 300

This patient has a large-fiber diabetic neuropathy. This is usually a length-dependent neuropathy, in which the patient has numbness and paresthesias that are painless. The distribution is symmetric, affecting hands and feet in a glove and stocking distribution. On examination, there is loss of vibratory sense and proprioception, as well as loss of deep tendon reflexes. Sensory ataxia may occur later in the course of the disease. Weakness may occur, but is not a prominent feature.

Answer 301

Tangier's disease

Answer 302

GM1, GM1b, GD1a AIDP variant

Answer 303

Dorsal interossei DAB: Dorsal, abduct

Answer 304

Palmar interossei PAD: palmar, adduct

Answer 305

Ulnar neuropathy. fifth digit abduction at rest.

Answer 306

Ulnar neuropathy due to compression in Guyon's canal

Answer 307

Radial neuropathy at the spinal groove

Answer 308

Radial neuropathy at the spinal groove

Answer 309

GQ1b AIDP variant

Answer 310

GD1b (GD1a in AMSAN and AMAN)

Answer 311

GM1 CIDP variant

Answer 312

Sensory neuronopathy

Answer 313

CIDP, AIDP

Answer 314

Saturday night palsy, proximal radial nerve injury prior to spiral groove

Answer 315

Familial amyloid polyneuropathy, FAP2, transthyretin

Answer 316

CIDP variant GM1 with conduction block (like AMSAN)

Answer 317

MADSAM CIDP variant

Answer 318

Charcot-Marie-Tooth (CMT)

Answer 319

CMT1, AD, demyelinating Second most common type is X-linked CMT

Answer 320

Heriditary neuropathy with liability to pressure palsies

Answer 321

Connexin 32 gene

Answer 322

Hereditary sensory and autonomic neuropathy

Answer 323

Primary erythromelalgia (can also occur in Fabry's disease)

Answer 324

GM1, GM1b, GD1a (like AMSAN, GM1 also with MMN with conduction block), GalNAc-GD1a AIDP variant

Answer 325

Familial amyloid polyneuropathy type 1, transthyrtein, consider Fabry's disease if X-linked inheritance pattern

Answer 326

Acute intermittent porphyria

Answer 327

Purplish lesion seen on trunk, scrotum, in Fabry's disease

Answer 328

alpha-galactosidase

Answer 329

Refsum disease Myoneurogastrointestinal encephalopathy **Neurogenic muscle weakness, ataxia, and retinitis pigementosa syndrome** Abetalipoproteinemia