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NEUROAlzheimer’s DiseaseEtiology and CourseAlzheimer disease is a progressive, degenerative disorder that is caused by a genetic defect in rare cases (see later), but is usually sporadic and of unknown cause. Abnormal metabolism, deposition, or clearance of two proteins—Aβ and tau—appears to be closely linked to pathogenesis.Familial related: β-amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2). Onset of the disease in these patients is typically between the ages of 30 and 60 years. Patients with Down syndrome (trisomy 21) also develop early Alzheimer disease (mean onset at age 50 years), which is thought to be related to an extra copy of the APP gene, located on chromosome 21Course:chronic neurodegenerative disorder usually in middle or late life characterized by progressive development of?cognitive dysfunction - memory loss, language difficulty, and executive dysfunction ?psychiatric and behavioral symptoms - such as depression, hallucinations, delusions, agitation?difficulty performing activities of daily living - basic or complexclinical progression of Alzheimer disease is thought to comprise a presymptomatic phase of up to about 10 years characterized by the deposition of amyloid plaques, followed by a symptomatic phase of up to about 10 years, during which tangle formation occursdeath typically occurs from 5 to 10 years after the onset of symptomsSigns/ Symptoms?typical pattern is gradual memory loss beginning with difficulty word finding, progressing to symptoms interfering with work and social activities?apathy (loss of motivation) common and should be distinguished from depression and loss of ability due to cognitive decline,1.Early manifestations— The term mild cognitive impairment (MCI) is sometimes used to describe the early phase of cognitive decline observed in patients who later receive a diagnosis of Alzheimer disease. Impairment of recent memory is typically the first sign of Alzheimer disease and may be noticed only by family members. As the memory disorder progresses over months to several years, the patient becomes disoriented to time and then to place. Aphasia, anomia, and acalculia may develop, forcing the patient to leave work or give up the management of family finances. depression apparent in the earlier stages of the disorder may give way to an agitated, restless state. Apraxias and visuospatial disorientation ensue, causing the patient to become lost easily. 2.Late manifestations—previously preserved social graces are lost, psychiatric symptoms, including psychosis with paranoia, hallucinations, or delusions, may be prominent. Seizures occur in some cases. Physical FindingsEarly ManifestationsPrimitive reflexes are commonly found. A frontal lobe gait disorder may become apparent, with short, slow, shuffling steps, flexed posture, wide base, and difficulty in initiating walking.Late manifestationsrigidity and bradykinesia. Rare and usually late features of the disease include:myoclonus,incontinence, spasticity,extensor plantar responses, hemiparesis.Mutism, incontinence, and a bedridden state are terminal manifestations. Eating problems, febrile episodes, dyspnea, pneumonia, and pain are frequent complications in the final months of lifeDiagnostic TestingLaboratory investigations can exclude other disorders, including reversible or otherwise treatable conditions. Cognitive testing may also be useful in helping to distinguish between Alzheimer disease and other causes of dementia. In patients with Alzheimer disease, the CT scan or MRI often shows cortical (especially medial temporal lobe) atrophy and enlarged ventricles, but such changes are nonspecific. Positron emission tomography (PET) scanning may reveal hypometabolism and hypoperfusion in the temporal and parietal lobes.?clinical criteria for probable Alzheimer disease dementia?patient meets clinical criteria for dementia?history of gradual onset over months to years?clear worsening of cognitive abilities?initial and most prominent cognitive deficits seen on history and exam may be eitheramnestic (most common presentation)nonamnestic (language, visuospatial or executive dysfunction presentation)?diagnosis of probable Alzheimer disease dementia should not be made if?onset of dementia related to stroke?radiologic findings of multiple or extensive infarcts or severe white matter hyperintensity burden?features of Lewy body disease (besides dementia)?features of frontotemporal dementia (behavioral variant)?features consistent with primary progressive aphasia (semantic variant or non-fluent/agrammatic variant)?evidence of other disease or medication effect that could be affecting cognitive abilitiesTreatmentNo treatment available to reverse or arrest disease progression.Drugs for improvement:Drug ClassDrugDoseToxicityGlutamate antagonistmay produce modest improvement in patients with moderate or severe Alzheimer disease.Memantine5 mg orally daily, increased by 5 mg each week to 10 mg orally twice dailyDizziness, headache, constipation, confusionAcetylcholinesterase inhibitorsymptomatic treatment of cognitive dysfunctionTacrine10 mg orally 4 times daily may be increased to 20 mg orally 4 times daily after 6 weeksAbdominal cramps, nausea and vomiting, diarrhea, hepatocellular toxicity (liver enzymes should be monitored twice monthly for 4 months)Donepezil5 mg orally at bedtime; may be increased to 10 mg orally at bedtime after 4-6 weeksNausea, diarrhea, vomiting, insomnia, fatigue, muscle cramps, anorexiaRivastigmine1.5-6 mg orally twice dailyNausea and vomiting, diarrhea, anorexiaGalantamine4-12 mg orally twice dailyNausea and vomiting, dizziness, diarrhea, anorexia, weight lossAntipsychotic drugs, antidepressants, and anxiolytics may be useful in controlling behavioral disturbances associated with Alzheimer disease. However, evidence for their effectiveness is sparse, and in some cases (risperidone, olanzapine) their use is associated with an increased incidence of stroke in elderly patients.Follow-UpReferral for neuropsychological testing may be helpful in the following circumstances: to distinguish dementia from depression, to diagnose dementia in persons of very poor education or very high premorbid intellectto aid diagnosis when impairment is mild.PERIPHERAL NERVE DISEASES_____________________________________________________________________________Bell’s palsyEtiology and CourseFacial weakness of the lower motor neuron type caused by idiopathic facial (VII) nerve involvement outside the central nervous system, without evidence of more widespread neurologic diseaseEtiologyIdiopathic, but likely infectious or post-infectious (herpes virus – HSV, VZV)occurs more commonly in pregnant women and diabeticsCourse: Weakness generally comes on abruptly but may progress over several hours or even a day or so71% show complete recovery in 3 weeks16% residual weaknessRecurrence: 7-15% over 10 yrsSigns/SymptomsFacial weakness is often preceded or accompanied by pain about the earDepending on the site of the lesion, there may be associated impairment of taste, lacrimation, or hyperacusis.There may be paralysis of all muscles supplied by the affected nerve (complete palsy) or variable weakness in different muscles (incomplete palsy).(Lack of forehead wrinkle)Physical FindingsNo abnormalities beyond the territory of the facial nerve.Diagnostic TestingDx based on clinical presentationWork Up:Test for lyme disease (serology testing)If bilateral facial palsy: think sarcoidosisMay check ACE levelOther conditions that can produce facial palsy include tumors, herpes zoster infection of the geniculate ganglion (Ramsay Hunt syndrome), Lyme disease, AIDS, sarcoidosis, or any inflammatory process involving the subarachnoid space, such as infective or neoplastic meningitisTreatmentSteroidTreatment with corticosteroids (prednisone 60 or 80 mg/d orally for 3 days, tapering over the next 7 days), beginning within 5 days after the onset of palsy, increases the proportion of patients who recover completely, significantly improving the chances of complete recovery at 3 and 9 months. Anti-viralno convincing evidence that treatment with acyclovir or other antiviral agents confers any benefit.Peripheral neuropathyEtiology and CourseEtiology?trauma - compression entrapment neuropathies?endocrine disorders - diabetes mellitus, uremia, hypothyroidism?infection - leprosy, zoster, diphtheria, Lyme disease, HIV, Q fever?Other - Paraproteinemia, sarcoidosis, neoplasms, nutritional deficiencies (thiamine, folic acid, vitamin B12 deficiency), connective tissue diseases, amyloidosis, multiple myeloma, Guillain-Barre syndrome, syphilis, HIV?toxic neuropathies – alcohol, chemotherapy drugs?hereditary neuropathies – Charcot-Marie-Tooth syndrome (most common familial motor and sensory abnormality, foot deformity common, braces for correction of foot drop useful, surgical management usually necessary for stability and cosmetic appearance of feet), Dejerine-Sottas disease, Refsum's disease, Riley-Day syndrome○ 30% of PN is related to diabetes○ 30-50% of PN is idiopathicSigns/Symptoms?numbness and paresthesias○ Numbness, or a feeling of walking on cotton wool or wearing a thick sock (feel like walking on uneven surface)?burning feet○ Pains that can be dull, constant and boring in type, or more spontaneous sharp, shooting, or stabbing in nature; a sensation as if walking on pebbles○ Tingling, pins and needles○ Hot or cold sensations (e.g., “burning feet”; “like walking on hot sand”)○ Allodynia (pain caused by an otherwise non-painful stimulus, such as light touch or stroking); this can be very troublesome at night when the feet and legs rub against the bedclothes○ Cramps in the calves and foot muscles.Additional history:?history of trauma consistent with compression entrapment neuropathies? risk factors for AIDS?history of tick bite or erythema chronica migrans (ECM) rash consistent with Lyme disease?patterns of neuropathy related to clinical disorders:?alcohol - pain, numbness and weakness of extremities?uremia - symmetrical distal mixed motor and sensory?hypothyroidism - distal sensory neuropathy manifested by burning sensation and paresthesias of limbs, delayed relaxation phase of DTR?HIV - 3 major forms of neuropathy with HIV ?distal symmetrical polyneuropathy, often appearing as burning pain in soles with dysesthesias and paresthesias of feet?inflammatory demyelinating neuropathy manifest by progressive weakness in ≥ 2 limbs, areflexia, and mild sensory loss?autonomic neuropathy symptoms include fainting, orthostatic dizziness, diarrhea, urinary dysfunction, and impotence?sarcoidosis - cranial nerve palsies usually facial nerve, polyneuropathy?neoplasms - sensory and sensorimotoryPhysical Findings?determine sensory vs. motor vs. mixed?determine number of nerves involved - mononeuropathy, polyneuropathy, mononeuropathy multiplex (mononeuropathy multiplex and/or palpable purpura strongly suggests vasculitis)?determine territory of neurological deficit?evaluate DTRs (decreased in root and peripheral nerve disease)Diagnostic TestingLab TestsAlthough routine screening with a panel of basic tests is often performed, those tests with the highest yield of abnormality are □ blood glucose (fasting)□ serum B12 with metabolites (methylmalonic acid, homocysteine)□ serum protein immunofixation electrophoresis or SPEP”EDX (Electrodiagnostic studies) □ may show up abnormal in 70% of patients□ sural sensory amplitude (63%)□ denervation changes on EMG of the ant tibialis (28%) of 90 patients, and the results of nerve conduction□ Four patients with normal EDX studies underwent skin biopsy had reduced intraepidermal nerve fiber density Nerve Biopsy□ Not done routinelyTreatmentTreatment is of the underlying cause, when feasible.Overall:○ First line§ Antidepressants§ Anticonvulsants○ Efficacy○ Adverse effects/tolerability/cost○ Second line§ Topical agents○ Opioids (last resort)○ Pain clinic referral?Conservative:Physical therapy helps prevent contractures, splints can maintain a weak extremity in a position of useful function. Anesthetic extremities must be protected from injury. To guard against burns, patients should check the temperature of water and hot surfaces with a portion of skin having normal sensation, measure water temperature with a thermometer, and use cold water for washing or lower the temperature setting of their hot-water heaters. Shoes should be examined frequently during the day for grit or foreign objects in order to prevent pressure lesions.avoid such behavior as leaning on elbows or sitting with crossed legs for lengthy periods.Neuropathic, burning pain simple analgesics, such as aspirin or nonsteroidal anti-inflammatory agentsgabapentin (300 mg orally three times daily, titrated up to a maximum of 1200 mg orally three times daily as necessary). Duloxetine (60 mg orally daily) venlafaxine (start 37.5 mg orally twice daily, and titrate up to 75 mg orally two to three times daily)severe hyperpathia or pain induced by minimal stimuli, Opioids may be necessary, but their use should be avoided as much as possible. The use of a frame or cradle to reduce contact with bedclothes may be helpful. episodic stabbing pains, gabapentin, pregabalin (100 mg orally three times daily), carbamazepine (start 100 mg orally twice daily, and titrate up to 400 mg orally twice daily), tricyclic antidepressants (eg, amitriptyline 10–150 mg orally at bedtime daily). Symptoms of autonomic dysfunction are occasionally troublesome. Postural hypotension ioften helped by wearing waist-high elastic stockings and sleeping in a semierect position at night. Fludrocortisone reduces postural hypotension, but doses as high as 1 mg/d are sometimes necessary in diabetics and may lead to recumbent hypertension. Midodrine, an alpha-agonist, is sometimes helpful in a dose of 2.5–10 mg three times daily. Erectile dysfunction and diarrhea are difficult to treat; a flaccid neuropathic bladder may respond to parasympathomimetic drugs such as bethanechol chloride, 10–50 mg three or four times daily.Guillain-Barre syndromeEtiology and CourseThis acute or subacute polyradiculoneuropathy sometimes follows infective illness, inoculations, or surgical procedures. There is an association with preceding Campylobacter jejuni enteritis. The disorder probably has an immunologic basis, but the precise mechanism is unclear.Course:?symmetric ascending weakness, proximal and distal, which evolves over days to weeks(1)?nadir of weakness within 2 weeks in 50% of patients, and by 4 weeks in 90%Signs/Symptomsmain complaint is of weakness varies widely in severity in different patients often has a proximal emphasis and symmetric distribution. It usually begins in the legs, spreading to a variable extent but frequently involving the arms and often one or both sides of the face. The muscles of respiration or deglutition may also be affected. Sensory symptoms are usually less conspicuous than motor ones, but distal paresthesias and dysesthesias are common, and neuropathic or radicular pain is present in many patientsprogressive weakness?usually symmetric ?progresses over period of days to weeks?can be proximal, distal, or combination?facial weakness often involved?bulbar and ocular nerves less commonly involved?sensory complaints common (but not sensory findings)?numbness and paresthesia affect extremities and spread proximally?pain may be prominent complaint in children?rare symptoms (5%) include?urinary retention?gastrointestinal complaints?constipation?gastric distention?diarrhea?fecal incontinencePhysical FindingsAutonomic disturbances are also common, may be severe, and are sometimes life-threatening; ?autonomic signs may be present?tachycardia most common?wide blood pressure changes (hypertension or postural hypotension)?bradycardia?cardiac arrhythmias?neurogenic pulmonary edema?changes in sweat?respiratory signs include?paradoxical breathing pattern due to diaphragmatic weakness?shallow respirationsHEENT: ?may have unilateral or bilateral facial paresis(1, 4)?ophthalmoplegia rare (reported in 5%)(4)Neuro: ?symmetric proximal and distal weakness?areflexia (or decreased deep tendon reflexesDiagnostic TestingEssentials of Diagnosis ?Acute or subacute progressive polyradiculoneuropathy.?Weakness is more severe than sensory disturbances. ?Acute dysautonomia may be life-threatening.Diagnostic Tools?lumbar puncture?minimum studies on cerebrospinal fluid (CSF) include?glucose?protein?cell count?bacterial cultures?CSF may be normal early (first few days), repeat lumbar puncture if Guillain-Barre syndrome (GBS) strongly suspected?The cerebrospinal fluid characteristically contains a high protein concentration with a normal cell content, but these changes may take 2 or 3 weeks to develop.?electrodiagnostic studies including nerve conduction velocity (NCV) can help confirm presence, pattern, and severity of neuropathy?electrocardiogram (ECG) monitoring if concern for arrhythmia (autonomic instability)(2)?stool cultures for Campylobacter jejuni(2)?nerve biopsy rarely indicatedMaking the DiagnosisRequired:?progressive weakness in both arms and both legs?areflexiaSupport DxDoubt DxExclude Dx?clinical featuresprogression of symptoms over days to 4 weeksrelative symmetrymild sensory symptoms or signscranial nerve involvement, especially bilateral weakness of facial musclesrecovery beginning within 4 weeks after progression ceasesautonomic dysfunctionabsence of fever at onset?laboratory findingshigh concentration of protein in cerebrospinal fluid (CSF)white count in CSF < 10/mm3typical electrodiagnostic features of peripheral demyelinating polyneuropathy including nerve conduction slowing or block?clinical featuressignificant asymmetry of weaknesspersistence of bladder or bowel dysfunctionbladder or bowel dysfunction at onsetsharp sensory level on examination?CSF findings> 50 mononuclear white blood cells/mm3presence of polymorphonuclear white blood cells?abnormal porphyrin metabolism?recent diphtheria?clinical picture consistent with lead neuropathy?diagnosis of botulism, psychogenic paralysis, poliomyelitis, or toxic neuropathy (including hexacarbon exposure)?purely sensory syndrome, without weaknessTreatmentPlasmapheresis best performed within the first few days of illness and is particularly useful for clinically severe or rapidly progressive cases or those with ventilatory impairment. IVIG (400 mg/kg/d for 5 days) equally helpful and imposes less stress on the cardiovascular system than plasmapheresis. Hospital admittancePatients should be admitted to intensive care units if their forced vital capacity is declining, and intubation is considered if the forced vital capacity reaches 15 mL/kg, the mean inspiratory force reaches –40 mm Hg, dyspnea becomes evident, or the oxygen saturation declines. Respiratory toilet and chest physical therapy help prevent atelectasis. Marked hypotension may respond to volume replacement or pressor agents. Low-dose heparin to prevent pulmonary embolism should be considered.Follow-UpWhen to Refer: All patients should be referred. When to Admit: All patients should be hospitalized until their condition is stable and there is no respiratory compromise.Myasthenia gravisEtiology and Courseautoimmune diseaseAttack acetylcholine receptors on post-synaptic neuron antibody-mediated, T cell-dependent immunologic attack at end plate of postsynaptic membranepenicillamine can cause myasthenia gravis90% of cases develop anticholinergic receptor antibodies70% of patients will have spontaneous resolution of myasthenia within 1 year of penicillamine discontinuationMost common NMJ diseaseCourse?can have remissions and exacerbations?about 85% of patients with initial presentation of only ocular symptoms will progress to generalized myasthenia within 3 years (involvement of bulbar muscles and extremities)(1)?maximum severity of disease often reached within first year in about two-thirds of patients(1)?myasthenic crisis (respiratory failure) occurs in about 20% of patients (usually during first year)(1)?worsening of myasthenia can occur with intercurrent systemic illness and other conditions including(1)?pregnancy?thyroid disease?fever?viral upper respiratory infection?medications that can result in impairment of neuromuscular transmissionSigns/SymptomsInitial symptom: ptosis or diplopia in two thirds.*10% purely ocularWeakness (skeletal muscles)□ Eye muscles□ Limb muscles□ Cranial-innervated muscles□ Diaphragm§ Weakness is variable: worst towards end of day§ Worsened by illness or medicationsNo painPhysical Findings?variable muscular weakness with fatigability?cranial nerve examination?may have asymmetric pattern of weakness of multiple extraocular muscles unexplained by single cranial nerve?pupil function should be normal?may elicit ptosis (drooping eyelid) by having patient gaze upward without blinking for extended amount of time?Cogan lid twitch sign?have patient rapidly change gaze from looking downward to primary position (mechanical center of eye range of movement)?positive Cogan twitch sign occurs when upper lid overshoots before resuming prior ptotic position?fluctuating weakness that may be present on exam includes?weakness of forced eye closure that can be overcome by examiner?patient may have expressionless facial appearance from weakness of facial muscles?tongue strength may be overcome as patient attempts to push tongue against cheek and examiner resists with finger through cheek?patient may be unable to hold air inside of inflated cheeks?nasal quality of speech from weakness of soft palate?neck flexors being overcome by examiner?motor exam?asymmetric weakness of muscles(1)?most commonly affected muscles(1)?dorsiflexors of foot?deltoids?triceps?finger and wrist extensorsDiagnostic TestingMaking the diagnosis: ?clinical history of fluctuating weakness with signs and symptoms worsening at end of day, combined with confirmatory testing such as?testing with edrophonium chloride (Tensilon test) resulting in unequivocal resolution of weakness?electrophysiologic testing with repetitive nerve stimulation or single-fiber electromyography?acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) antibodies□ Antibodies:For diagnosis□ Antibodies to Acetylcholine receptor (Ach-R) on muscle ? 80% generalized? 50-70% ocular? Complement-mediated alteration of endplate? Reduction in concentration of receptors□ Antibodies to muscle specific tyrosine kinase (MuSK) 10% ? facial, respiratory, and proximal muscle weakness more likelyTreatment§ Aceytlcholinesterase inhibitor□ Blocks enzyme , lets more ach around NMJ§ Immunotherapy□ MAINSTAY TREATMENT: prednisone, etc.?avoid (or use with caution) many drugs which may induce or exacerbate myasthenia gravis, or interfere with drugs used to treat myasthenia gravis?ocular myasthenia?acetylcholinesterase inhibitors should be first-line treatment (EFNS Good Practice Point)?nonmedication treatments for ocular myasthenia include?eye patching?lid crutches?in patients with ocular myasthenia, little evidence to support or refute use of corticosteroids and/or azathioprine to prevent progression to generalized myasthenia (AAN Level U)?generalized myasthenia?acetylcholinesterase inhibitors?used for treatment of mild generalized disease?should be first-line treatment (EFNS Good Practice Point)?corticosteroids?often used as initial immunotherapy, usually after inadequate response to acetylcholinesterase inhibitors?oral corticosteroids should be first choice drug when immunosuppressive medication is necessary for treating myasthenia (EFNS Good Practice Point)?may see transient weakness and myasthenic exacerbations during first 2 weeks when beginning corticosteroids?may also be used to provide short-term benefit (level 2 [mid-level] evidence)?immunosuppressive agents, such as cyclosporine or azathioprine, may be effective but have risk of severe adverse effects?tacrolimus should be tried in patients with poorly controlled disease, especially ryanodine receptor (RyR) antibody-positive patients (EFNS Level C)?IV immunoglobulin (IVIG)?IVIG may be used for treatment of refractory exacerbations of myasthenia gravis, but insufficient data for role of IVIG for chronic management of myasthenia?IVIG and plasma exchange appear to be equally effective in treatment of myasthenia gravis exacerbations (EFNS Level A)?IVIG may provide short-term improvement in strength scores for patients with worsening or symptomatic myasthenia gravis (level 2 [mid-level] evidence)?plasmapheresis associated with disease improvement, but may not be more effective than prednisone or IVIG in patients with myasthenia gravisTrigeminal neuralgiaEtiology and CourseDemyelination of trigeminal nerve leading to ectopic transmission of nerve impulses, which are more prone to stimulation by light touch, etc*Vascular compression (usually this!)on the nerve root by aberrant vessels, usually the superior cerebellar arteryMultiple sclerosis (especially in patients under 40)Nerve root tumorsAV malformations: arterio-venous Bony compressionsCourse? Spontaneous remissions, frequently returnsSigns/Symptoms? Episodic, sharp, lancinating (piercing, stabbing) facial pain in trigeminal nerve distribution (this is secondary to sensory information, not motor related)? Primarily 2nd and 3rd branches ? Maxillary branch (V2) most often○ Corner of mouth that radiates to eye? Then mandible..? Ophthalmic branch (V1) least often? Unilateral (right > left)? Duration of 2-3 seconds or minutes “tic”? Precipitated by touch, chewing, talking, drafts, or shaving (trigger points)Physical Findings? Normal PE except for pain in trigeminal nerve distribution.? Physical abnormality suggests underlying pathology such as multiple sclerosis or brainstem neoplasm, not trigeminal neuralgia.? Normal neurologic examination? All cranial nerves intact, including CN VDiagnostic Testing? Trigeminal Neuralgia confirmation is based upon the characteristic history and a normal neurological examination? Consider an MRI to exclude an uncommon mass lesion, plaques of multiple sclerosis, aberrant vessel compressing the nerve roots, or an atypical presentation.TreatmentAnticonvulsantsCarbamazepine (Tegretol)* Initial treatment of choiceCarbamazepine is classed as an anticonvulsant drug. It is normally used to treat epilepsy. TN is not epilepsy. However, the effect of carbamazepine is to quieten nerve impulses and it often works well for TN. There is a good chance that carbamazepine will ease symptoms of TN within 1-2 days. A low dose is started and built up gradually until a dose is reached that stops the pains. You should then take it regularly to prevent pains from returning. The dose of carbamazepine needed to control the pains varies from person to person.It is common to take carbamazepine until about a month after the pains have stopped. The dose may then be reduced gradually and stopped if possible. After this, there is often a period when pains do not occur for some time (remission). However, the pains are likely to return at some time in the future. Treatment can then be restarted. Some people find that carbamazepine works well at first but less well over the years.Phenytoin (Dilantin)Gabapentin (Neurontin)?Muscle relaxantsBaclofen (Lioresal)Primary indication for MS related spasticity or spinal cord disease.Used in conjunction with Carbamazepine??Other TreatmentsBotoxTopical capsaicin (from chili peppers)Sumatriptan (serotonin agonist: decrease inflammation of arteries) Intranasal lidocaineAcupuncture?Surgical TreatmentPercutaneous (less invasive, but not as good results)Radiofrequency rhizotomy Need neurosurgeon and anesthesiologist (need patient asleep for needle insertion and awake: know where to ablate)With rhizotomy: have numbness! (people would prefer this over pain however)Gamma knife stereotactic radiosurgeryLess long acting resultsRecurrence is commonOpen techniquesPartial trigeminal rhizotomy Cut sensory root rather than ablationRisk: facial numbness that is (more profound than ablation)(Note: ?rhizotomy?is a term chiefly referring to a neurosurgical procedure that selectively destroys problematic nerve roots in the spinal cord)Microvascular decompression (used more; aka MVD)Longest lasting persistent reliefNote: Vascular compression is a substantial physical contact between a cranial nerve (one of the nerve trunks exiting/entering the brainstem underneath the brain hemispheres) and one of the brainstem's Arteries pulsate… if nerve is sensitive, they get shock of pain. So here, if there is compression of superior cerebellar artery, place teflon pad between the two--> gives patient more constant relief. Follow-UpConsultation and referral: ?neurology for medical management and evaluation?neurosurgery in cases of medication failureHEADACHES_______________________________________________________________________________________________ClusterEtiology and CourseEtiology:?cause of primary cluster headache not clear; Often precipitated by alcohol or volatile substances?causes of secondary cluster headache may include?pituitary tumor?carotid artery dissection?cavernous sinus lesionCourse:?episodic cluster headache: attacks occur in bouts or clusters lasting several weeks to months separated by remission periods lasting ≥ 1 year?chronic cluster headache: attacks occur without substantial remission periods?attacks last 15 minutes to 3 hours?usually occur in bouts or clusters, usually recur on the same side in any given patient.Signs/Symptomsexcruciating unilateral headache characterized by sharp, piercing, throbbing, or burning periorbital painrapid onset with progression to excruciating pain over few minutespain usually at maximum intensity for duration of attack and then ends abruptlyorbital or supraorbital : usually around the eye, with tearing. may cause patient to wake from sleepOther:?restlessness or agitation in 70%-93%, patients often pace or sit and rock back and forth Patients tend to pace and apply pressure to the eye?photophobia in 54%-64%?phonophobia in 43%?osmophobia in 26%?nausea in 28%-50%?vomiting in 23%?aura manifestations reported in about 20% of patients with cluster headacheAutonomic symptomsPhysical Findingsipsilateral cranial autonomic signs accompany headache in about 97% of patients and may include?lacrimation?ptosis, may persist between attacks?miosis, may persist between attacks?conjunctival injection?rhinorrhea?nasal congestion?edema of face and eyelid?facial sweatingDiagnostic Testing?cluster headache is diagnosed by characteristic clinical features including:?attacks of severe unilateral pain in the periorbital or temporal region, usually with?ipsilateral cranial autonomic signs?restlessness or agitation?attacks last 15-180 minutes and occur from once every other day to 8 times per day?may be episodic or chronic?consider cranial computed tomography or magnetic resonance imaging at time of initial diagnosis or if abnormal neurologic findings present on examTreatmentAcute Abortive therapy:1st LineOxygen therapy (works best)100% oxygen at ≥ 7 L/minute for ≥ 15 minutes via nonrebreathing face mask (flow rate of ≥ 10 L/minute or up to 15 L/minute may be needed)Triptans?sumatriptan 6 mg subcutaneous injection ?zolmitriptan 5 mg or 10 mg intranasal spray2nd Line?zolmitriptan 5 mg or 10 mg orally ?sumatriptan 20 mg intranasal spray?octreotide 100 mcg subcutaneously?intranasal lidocaine 4%Otherdihydroergotamine, ergotamine tartrate, somatostatin, and prednisonePreventative: Verapamil ?verapamil 80 mg orally 3 times daily with increases by 80 mg/dose every 2 weeks to maximum of 960 mg/day is first-line treatmentif beginning verapamil, obtain baseline electrocardiogram (ECG) and repeat ECG 10 days after any dose increases (with particular attention to PR interval) due to relatively high incidence of heart block associated with verapamilLithiumdosed to maintain plasma level between 0.6 and 1.2 mmol/LOthers:? capsaicin, topiramate, sodium valproate, gabapentin, methysergide, and baclofen?corticosteroids can be used for short periods if attacks are short or as temporizing measure until another medication is established with maximum dose dependent on efficacy and tolerabilityFollow-UpConsultation and referral: consider neurological or headache specialist assessment for suspected casesFollow-up: patients should have long term follow-up and be evaluated when attacks recurMigraineEtiology and CourseClassification?migraine without aura (formerly called common migraine)?migraine with aura (formerly called classic migraine)?typical aura with headache?typical aura without headache?hemiplegic migraine - migraine with aura including motor weakness?familial hemiplegic migraine?sporadic hemiplegic migraine?migraine with brainstem aura (formerly called basilar-type migraine)?retinal migraine?chronic migraine - headache ≥ 15 days/month for > 3 months, including migraine features ≥ 8 days/monthEtiology:unknownsome genetic component: Autosomal dominant inheritance of migraine occurs in several well-recognized syndromes, including familial hemiplegic migraineCourse:?duration of headache (usually 4-72 hours)duration and severity of migraine attack may be predicted by characteristics of previous migraine attacks and timing of abortive medicationsmigraine episodes usually less frequent and less severe with ageSigns/ Symptoms?headache or pulsating headache?may have vomiting, photophobia, sonophobia (phonophobia), nausea?presence of aura (focal neurologic symptoms which usually precede or accompany headache phase) ?aura typically develops over 5-20 minutes and lasts < 1 hour?visual symptoms most common?simple auras include flashes (phosphenes), specks, geometric forms, shimmering, or scotomata?more complicated auras can include fortifications (stellate-shaped phenomena), teichopsia (jagged shimmering visual phenomena), micropsia, macropsia, mosaic vision?focal numbness (usually begins in hand and migrates up arm and to face)?weakness (rare and if present usually accompanied by sensory symptoms)?presence of less common phenomena including?apraxia?aphasia?agnosia?altered consciousness with deja vu or jamais vu?accompanying features that can include?nausea, vomiting, or anorexia?sensory hypersensitivity (patients prefer dark, quiet room)?diarrhea, sweating, blurred vision?common features of depression, fatigue, anxiety, irritability, impaired concentrationPhysical Findings?normal physical exam between episodes?warning signs of more serious illness may include fever, hypertension (but may occur due to pain), bradycardia?look for focal findings (such as ataxia, nystagmus, hemiplegia, dysarthriaDiagnostic TestingBased on clinical presentation:Without aura (MO)(common migraine)? A. At least five headache attacks lasting 4 - 72 hours (untreated or unsuccessfully treated), which has at least two of the four following characteristics:○ 1. Unilateral location○ 2. Pulsating quality○ 3. Moderate or severe intensity (inhibits or prohibits daily activities)○ 4. Aggravated by walking stairs or similar routine physical activity? B. During headache at least one of the two following symptoms occur:○ 1. Phonophobia and photophobia○ 2. Nausea and/or vomitingWith Aura (MA)(classical migraine)? A. At least two attacks fulfilling with at least three of the following:○ 1. One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem functions○ 2. At least one aura symptom develops gradually over more than four minutes, or two or more symptoms occur in succession○ 3. No aura symptom lasts more than 60 minutes; if more than one aura symptom is present, accepted duration is proportionally increased○ 4. Headache follows aura with free interval of at least 60 minutes (it may also simultaneously begin with the aura? B. At least one of the following aura features establishes a diagnosis of migraine with typical aura:○ 1. Homonymous visual disturbance○ 2. Unilateral paresthesias and/or numbness○ 3. Unilateral weakness○ 4. Aphasia or unclassifiable speech difficultyOverview of Imaging?neuroimaging not usually recommended for patients with migraine and normal neurologic exam ?testing should be avoided if it will not lead to change in management of migraine?neuroimaging (computed tomography [CT] or magnetic resonance imaging [MRI]) recommended in patients with:?unexplained abnormal neurologic signs (AAN Grade B)?atypical headache features or headaches that do not meet specific diagnostic criteria (AAN Grade C)?no specific recommendation made regarding presence or absence of neurologic symptoms (AAN Grade C), but risk factors for intracranial pathology in acute headache setting include?acute onset?occipitonuchal location?age > 55 years?associated symptoms?abnormal neurologic examTreatmentAcute Abortive Tx:Mild-Moderate?acetaminophen 1,000 mg relieves pain in acute migraine ?nonsteroidal anti-inflammatory drugs (NSAIDs) are reasonable first-line treatment effective NSAIDs includeibuprofen naproxen ?acetaminophen/aspirin/caffeine combination (Excedrin Migraine)is reasonable first-line treatment may be more effective than ibuprofen alone or oral sumatriptan ?acetaminophen/isometheptene/dichloralphenazone combination (Midrin) may also be used for first-line treatment Moderate-Severe orUnresponsive Mild-Moderate?triptansall marketed oral triptans may provide pain relief at 1 hour and eliminate pain at 2 hours for migraine patients with nausea and vomiting can be given parenteral triptans (intranasal or subcutaneous) ?sumatriptan (subcutaneous or intranasal) associated with faster headache relief but more recurrent headaches than dihydroergotamine (subcutaneous or intranasal)?dihydroergotamine (DHE) may be effective subcutaneously, IV, intramuscularly or via nasal spray Anti-emetics?may be effective as monotherapy for acute migraine?prochlorperazine (Compazine)IV, intramuscularly, or rectally appears effective for acute migraine may be more effective than IV ketorolac or subcutaneous sumatriptan ?metoclopramide (Reglan) IV effective for acute migraine but may be less effective than other antiemetics Preventative Tx:?start medications at lowest effective dose and increase dose gradually until benefits achieved or limited by adverse effects?adequate trial of medication may take 2-3 monthsBeta blockerspropranolol (target dose 80-160 mg/day) metoprolol (target dose 100-200 mg/day)Tricyclic antidepressantsamitriptyline (target dose 10-100 mg/day)nortriptyline considered similar to amitriptylineAnti-convulsantstopiramate (target dose 50 mg twice daily)Otherbutterbur extract 75 mg twice daily, but use only commercial products which have removed toxic alkaloids(See appendix for others)Follow-Up?Proactive long-term follow-up procedures should be instigated for all migraine patients:?A headache diary should be used to capture the patient's pattern of headaches over time.?Patients who do not respond to repeated courses of acute and prophylactic medications should be referred to a neurologist or headache specialist for care.TensionEtiology and CourseMost common type of primary headacheEtiology:?muscle contraction headache; compression of greater occipital nerveCourse?may be subclassified as episodic (occurring 1-14 days/month) or chronic (≥ 15 days/month for > 3 months)Signs/ Symptomsbilateral pain of non-throbbing quality, typically begins at occiput, radiates around head bilaterally like a tight vice-like bandnot aggravated by physical activity. generally no nausea, vomiting, aura, family historypatient often awakes with headache, can last for monthsPhysical Findings?scalp muscle tenderness may be found?tender (and spasm of) posterior cervical and occipital muscles, contraction/insertion painDiagnostic Testing?tension-type headache is diagnosed based on clinical features, including some of the following features?bilateral headache?mild to moderate intensity?pressing or tightening quality (non-pulsating)?not aggravated by routine physical activity?absence of nausea and vomiting?may have photophobia or phonophobia (but not both)Treatment? Relaxation therapy, physical therapy, stretching?warm moist heat, massage of scalp and neck muscles by another person or physical therapy to relax musclesAcute: OTC analgesics ?limit use of analgesics to 2-3 times per week?document daily use of over the counter and prescription analgesics over time?avoid use of combination analgesics, or opioids in patients with frequent headachesVarious analgesics with similar efficacy?ibuprofen 200-800 mg orally 3 times daily?aspirin or acetaminophen 1,000 mg orally once or 650 mg orally every 4-6 hours as needed?combination analgesics may be useful for moderately severe headaches unresponsive to acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs)?ibuprofen 400 mg plus caffeine 200 mg orally appears faster and more effective than either component alone?ketoprofen 25 mg orally appears as effective as acetaminophenPreventative: ?begin with low dose and titrate every 1-2 weeks until target dose reached or adverse side effects?therapeutic effect may take 2-3 months to be achieved?maintain headache diary?after 6 months gradual titration to lower doses monitoring headache patternTCA?tricyclic antidepressants considered first-line treatment in most cases (level 2 [mid-level] evidence)?target dose amitriptyline 75-100 mg/day or nortriptyline 75 mg/day orally?combining tricyclics and stress management therapy appears more effective than either treatment aloneSSRI?selective serotonin reuptake inhibitors (SSRIs) may be less effective than tricyclic antidepressants (TCA)Beta BlockerPropanolol useful in some casesFollow-Up?referral to headache clinic care appears to reduce headache-related disabilityINFECTIOUS DISORDERS___________________________________________________________________________________? MeningitisBacterial MeningitisEtiology and CourseGroup B StrepOccurs in newborn (1st week of life)Pregnant women can transfer Group B strep to newborn during deliveryLife threateningPregnant women who test positive for Group B Strep during their pregnancy need to be given IV antibiotics (PCN G, Ampicillin, Cefazolin, or Vancomycin) during labor or when their membranes rupture.Strep PneumoniaeCauses meningitis in all age groups, therefore it’s the most common cause of bacterial meningitisBacteremia frequently occurs from nasopharyngeal colonization alone, though it can be due to pneumococcal pneumoniaGram (+) diplococciNeisseria meningitidis (meningococcus)Second most common organism causing bacterial meningitis; Group C most common in U.S.Up to 40% of persons are nasopharyngeal carriers of meningococci, yet disease develops in relatively few of these persons.Primarily causes disease in children and young adults (college age kid)Meningitis can occur alone or in association with syndrome of meningococcal shockShock may be first thing you seeGram (-) diplococci** There is no vaccine coverage for type B (which causes 1/3) of all meningococcal cases in the U.S. (not sure why there was spike in 1995)Haemophilus influenzaeOnly Type B causes meningitisSince children are now routinely immunized with the conjugated Hib vaccine, H. influenzae meningitis has become rare, except in the unimmunized populationThink about immigrant population here. Affects the age group 1 month – 6 years of age (pediatric population mostly)Gram (-) coccobacilliSpirochetesTreponema pallidum (Syphilis)Borrelia burgdorferi (Lyme Disease)Course:Modes of OnsetAcutethis is who we worry about25% of cases begin abruptly with fulminant illness, high mortalityProgressiveMost common onset is progressive meningeal symptoms over 1-7 daysSuperimposedBlends inMeningitis may superimpose itself on 1-3 weeks of an upper respiratory illness (most difficult to diagnose) complications (when they occur) usually happen within the first 2–3 days of treatment and are exceedingly rare after 3 or 4 days of appropriate antimicrobial therapySigns/SymptomsThe classic triad of fever, stiff neck and AMS changes only occurs in ~ 45% of patients. However, nearly all patients with bacterial meningitis will have 2 of the following symptoms highlighted in yellow below. ?Rapid and Progressive onset of: (usually two of yellow)Headache FeverNeck and/or back pain and stiffnessStiff neck is absent in 20% of patients.Most commonly in the very young, old, and the comatoseConfusionPhotophobia+Kernig’s and Brudzinski’s signsCSF abnormalities?Other Findings:A petechial or purpuric rash is found in 50% of patients (with meningococcal etiology)May look like rickettsial disease: Rocky mountain spotted feverSeizuresApproximately 20% of patients have seizuresSeizures (focal or generalized) 20-30% of patientsResult from readily reversible causeshigh fever in infantspenicillin neurotoxicity when large doses are given intravenously in the presence of renal failureFocal Neurological Findings20% of patients have focal neurologic findingsCranial Nerve abnormalities: III, IV, VI or VII Usually resolve after recoveryTransient hearing loss (10%)-sensorineuralPersistent hearing loss (10%)Brain swelling and increased CSF pressure associated with seizures, abnormal reflexes, coma, bradycardiaFocal cerebral signs such as hemiparesis, dysphasia, visual field defectsResidual neurologic damage remains in 10-20% of patients who recover from bacterial meningitisDevelopmental delay and speech defects are each observed in 5% of childrenPhysical Findings(See above)Diagnostic TestingOverall:? Not difficult in a febrile patient with meningeal symptoms and signs developing in the setting of a predisposing illness? Less obvious in the elderly, obtunded patient with pneumonia, or the confused alcoholic patient in impending delirium tremors? Examination of the CSF should be carried out promptly whenever there is a question of meningitis, but beware of the criteria for obtaining a CT HEAD vs. Lumbar puncture.immunocompromisedhistory of central nervous system disease (such as stroke, mass lesion, focal infection)papilledemafocal neurologic deficit includingfixed dilated pupilgaze palsyweakness of extremityvisual field cutnew onset seizure ≤ 1 week prior to presentationabnormal level of consciousnessTestingLabs:CBCBlood Cultures: generally, 3 different sets over 24 hours….remains controversialCMP: see if there is metabolic cause (liver cause potentially?)? CT scan (head): is there something going on in headIf you suspect that the patient has a space occupying lesion, (brain abscess, subdural hematoma, subdural abscess) then a CT Scan must be done to prevent brain stem herniation. On PE, you might see papilledema, coma, seizures or focal neurological findings. Do not delay starting antibiotics because you are waiting for the CT scan..draw blood cultures and start antibiotics and steroids even before cerebrospinal fluid is obtained for culture to avoid delay in treatment. Antibiotics given within 4 hours before obtaining CSF probably do not affect culture results. Lumbar PunctureProcedureContraindications:PapilledemaNew onset seizureFocal neurological deficitCoagulopathySevere impairment of LOCNote:Should these conditions be encountered, consider CT HEAD first to r/o Brain abscess . Performing an LP first could lead to brainstem herniation if a space occupying lesion is presentShould there be a delay in radiology, then proceed with drawing blood cultures and administer IV antibiotics. If none of these, then go ahead with LP. ?CSF Analysis: Normals:WBCs: nl: 0-5 lymphocytes (high 500-10,000)Usually contains 500-10,000 WBCs per microliter with >90% neutrophilsGlucose: nl 45-85 mg/dl (2/3rds of serum glucose) (low<45) Glucose content falls below 40 mg/dL (normal range 45-85 mg/dL) **A low glucose level can indicate infection, but also subarachnoid hemorrhage.Protein: nl 15-45 mg/dl (high > 50)The protein level rises above 150 mg/dL (nl range 0-1 month <150 mg/dL, 1-6 months 30-100 mg/dL, 6 months and up 15-50 mg/dL)pH: nl 7.31Opening Pressure nl 70-180 mm H2O (high >200)Markedly elevated pressuresCulture and Gram stainThe Gram-stained preparation of CSF is positive in 80-88% of cases. May be negative in N. meningitidis, H. influenza, or L. monocytogenes as these bacteria may develop atypical forms in the CSFCultures of CSF (the one we want to rely on), blood, fluid expressed at purpuric lesions and nasopharyngeal swabs have a high yield. Note: If a patient has been on antibiotics, obtaining a culture from a nasopharyngeal swab may yield positive findings as antibiotics cannot reach a high level of concentration in nasopharyngeal secretions **Note:If interpretation of the gram stained CSF is not clear, then broad spectrum antibiotics should be started while awaiting the results of culturesNo need to repeat Gram Stain?Overview?Opening PressureWBCProteinGlucoseNormal70-1800-5 lymphocytes15-4545-85Bacterial MeningitisElevated (above 200)500-10,000 PMNElevated (above 150)Decreased (below 40)Neighborhood ReactionvariableVariably increasedNormal or highNormalNote: Neighborhood reaction = denotes a purulent infectious process in close proximity to the CNS that spills some of the products of the inflammation (WBC’s and protein) into the CSF. Ex) brain abscess, osteomyelitis of the vertebrae, mastoiditisTreatment? Emergent lumbar puncture for gram stain and culture of CSF.? Obtain blood work (CBC, CMP, blood cultures)? Important: PROMPT institution of appropriate antibiotics? If lumbar puncture must be delayed while awaiting results of an imaging study to exclude a mass lesion, then Ceftriaxone (Rocephin) is given IM/IV (IV is preferred) after blood cultures are obtained.Age GroupCommon BacteriaStandard Therapy18-50 yearsS. pneumoniae N. meningitidisCefotaxime or ceftriaxone + VancomycinOver 50 yearsS pneum./ N.meningitidis L.isteria monocytogenes/Gr(-) bacilliAmpicillin, cefotaxime or ceftriaxoneImpaired cellular immunityL. Monocytogenes Gram (-) bacilli, S. pneumoVancomycin + Ampicillin + cefepimePost-surgical/post traumaS. aureus, S. pneumo, Gram (-) bacilliVancomycin + ceftazidime or cefepime?In areas where penicillin-resistant pneumococcus is prevalent , vancomycin 10-15 mg/kg IV every 6 hours should be included in the regimen.The usual dose of cefotaxime is 2 gr every 6 hours and that of ceftriaxone is 2 gr every 12 hours. If the organism is sensitive to penicillin then 3-4 million units IV every 4 hours is given.The dose of ampicillin is usually 2 gr IV every 4 hoursThe dose of Ceftazidime is given in a dose of 50-100 mg/kg every 8 hours up to 2 grams every 8 hoursThe dose of vancomycin is 10-15 mg/kg every 6 hoursAseptic MeningitisEtiology and Course?80%-85% enterovirus (Coxsackievirus B, mumps, echovirus), HIV, HSV2, EBV, mumps virus, rarely lymphocytic choriomeningitis virus (LCMV)? Other causes of aseptic meningitis:? Tuberculosis, mycobacterium, syphilis, Lyme, Ehrlichiosis, RMSF, medications (NSAIDs)? (don’t give same CSF analysis like previous ones we've talked about)Course:? Full recovery typically in 1-2 weeks after onset? Fatigue, lightheadedness and weakness may persist for months in some patientsSigns/Symptoms?intense headache, fever, malaise, myalgia, photophobia; occasionally anorexia, nausea, vomiting? Acute onset of headache, fever, stiff neck, chills, n/v, and malaise with CSF pleocytosis (the presence of more cells than normal (often denotes leukocytosis or lymphocytosis)) over a few hours or could evolve over a few days? Not as "sick" as bacterial folks. ? If patient develops changes in consciousness, seizures, or focal neurological signs (lots of neurological things) then the diagnosis will be changed to encephalitis.○ Usually in meningitis, brain is working fine but they have infection. With encephalopathic patients, their brains are not working so well. ? Additional symptoms may suggest a particular infectious agent, i.e. mumps, herpetic lesions, HIV? MUST LOOK ELSEWHERE. Look at whole body!Physical FindingsGeneral physical: ?no change in mental status, no seizuresNeck: ?terminal nuchal rigidity (can't bend neck)Neuro: ?no focal neurological signs?meningeal signs are unreliable for diagnosing or ruling out meningitis ?meningeal signs ?nuchal rigidity?Brudzinski sign - rapid flexion of neck elicits involuntary flexing of knees in supine patient?Kernig's sign - resistance to knee extension following flexion of hips and knees by doctorPhysical Exam Clues:? Meningeal signs? Neck stiffness (Kernig’s or Brudzinski’s signs)? Parotitis – may suggest Mumps in an unvaccinated patient? Ulcerative genital lesions – may suggest HSV-2 infection? Oropharyngeal thrush - May suggest HIV infection? Rash (if they have one, what is it?)○ Coxsackievirus=maculopapular and nonpruritic○ Echovirus=petechial○ Herpes=vesicular○ Lyme=Erythema Chronicum migrans ○ Syphilis = diffuse maculopapulaDiagnostic TestingLabs to include, but not limited to:? CBC with differential, ? ESR,? ANA, ? RF, ? Lyme titer, ? VDRL (RPR), ? TST (tuberculin skin test), ? FTA-ABS (fluorescent treponemal antibody – absorption (tests for Syphilis))Imaging studies? CXR (PA and Lateral)? CT scan CSF studies? Gram’s stain, bacterial culture (negative)? Acid fast bacillus (microscopy very low yield, culture has sensitivity of only 60%)? Cryptococcal antigen? Cell count, protein, glucose , VDRL, FTA-ABS, Cytology? 10-500 mononuclear WBCs/microliter with early neutrophilia >50% and late neutrophilia <20%. ? Glucose is normal, may be minimally depressed in mumps, echovirus, HSV ? Protein <100 mg/dL (elevation is > 50)? Pressures may be elevated? Other:? Coxsackievirus and echoviruses can be isolated from stool or CSF? Mumps virus can be isolated from throat swabs, saliva or CSF? HSV-2 can be isolated from genital lesion swabs? Serum WBC usually is not elevated, but can be low or high? CXR and TST placement to rule out TBDx: Based on clinical presentation, complete and thorough History & Physical examination and CSF findings (or lackthereof)TreatmentGenerally benign and self-limitedSupportive care?Need to be vigilant as viral meningitis can be progressive?Effective antiviral therapy (IV Acyclovir) is available against: HSV-1 and 2, (Acyclovir)Varicella (Acyclovir) cytomegalovirus. (Ganciclovir)? EncephalitisEtiology and CourseA large number of viral and non-viral agents can cause encephalitis?Seasonal occurrence helps to limit the differential diagnosisArthropod-borne viruses peak in the summer (West Nile, Western Equine Encephalitis)Geographic distributionWest nile is most concentrated in upper mid-west** West Nile Virus is the most commonly diagnosed arboviral infection of the CNS. Four main sources: humans, horses, mosquito, birdHSV (herpes simplex virus) most frequent, treatable, and devastating cause of severe focal encephalitis. Implicated in 10% of all cases in North America. 70% mortality rate if left untreated.YOU HAVE TO BE SUSPISCIOUS AND LOOK!CSF Findings:0-1000 WBC/microliterProtein < 100 mg/dL (moderately high)Glucose normalCSF titers of antibody to HSV may show a fourfold diagnostic riseSigns/Symptoms? Headache? Fever? Neck and/or back stiffness? Altered sensorium (AMS)? Delirium? Behavioral abnormalities? Seizures? Focal neurological deficitsPhysical Findings? Pertinent Physical Exam Clues? Parotitis (parotiditis) – suggests the diagnosis of Mumps? Flaccid Paralysis with maculopapular rash suggests West Nile Virus? Tremors of the eyelids and extremities may suggest West Nile or St. Louis encephalitis ? Hydrophobia, hyperactivity suggests encephalitic rabies.? Grouped vesicles in a dermatomal pattern suggests varicella zosterDiagnostic TestingViral cultures of stool, throat, CSF and brain biopsy specimens may be helpful, but results may come too late to guide initial treatmentTreatmentIf HSV, if left untreated, has a high mortality rateAcyclovir therapy treatment of choiceImproves survival and lessens morbidityPrognosis is favorable in patients<30 years old with preserved mental status at time of presentationFor other causes of encephalitis, treatment is supportive.MOVEMENT DISORDERS__________________________________________________________________________________Essential tremorEtiology and CourseEtiology?unknown?may be a family of diseases with clinical and pathological heterogeneity depending on associated features such as cognitive impairment and personality changesVariety of studies show different results on familial tendencyCh 3q13 Icelandic kindredCh 2p22-25 American kindredMore common than PD tremorIncidence increases with age, but bimodal distribution of onset (20s and 60s)Course:Insidious onsetMay appear with minor symptoms early, then level off with a phase of worsening many years later"Oh I think I've had it my whole life"NOT associated with increased morbidity/mortalitySigns/SymptomsPatient complains of tremor during activities (usually during use of fine motor skills).How it is different than PD!!! Postural and kinetic componentsWorsen when trying to point to something or pour a glassDisappears or attenuates with rest.?Upper extremities (distal > proximal), head, voiceMuch more symmetrically than PD (unusual if just one hand, for example)"yes or no" tremorLower extremities, face, trunkRare to have it here; if it is here, then UE will be really badOther characteristics? Frequency of 4-12 Hz? Largely symmetrical? Cogwheeling may be present as “pseudocogwheeling”? "pseudo cog wheeling": feel ratcheting as you move arm up and down (may think its rigidiity)? NO parkinsonian signs: NO POSTURAL INSTABILITY, BRADYKINESIA, or RIGIDITY? Can enhance with ? Handwriting? Archimedes spiral? water pouringPhysical FindingsGeneral physical: tremor often of flexion/extension type(1, 2)tremor frequency usually 4-12 Hertz (Hz, cycles/second) and inversely related to age may have accompanying titubation (head tremor)(1, 2)tremor usually asymmetric HEENT: may have tremor of head (75% of head tremors were 'no-no' type), jaw, facial muscles, tongue and/or voice eye movement abnormalities may occur, based on 14 patients with essential tremor and 11 age-matched controlsExtremities: hands and arms commonly affected(1)rare involvement of lower extremities(1)Neuro: postural tremor seen with outstretched arms(1)kinetic tremor brought on by writing or with finger to finger to nose as patient approaches final target(1)look for resting tremor, bradykinesia, rigidity (features consistent with Parkinson’s disease rather than essential tremor)(2)tandem gait abnormalities associated with essential tremorDiagnostic Testing?usually clinical diagnosis based on history and physical exam?thyroid function testing (TSH) for hyperthyroidism in patients with tremor(1, 2)?tests to rule out Wilson’s disease (ceruloplasmin, serum copper, liver function tests) in patients < 40 years old(1, 2)?striatal dopamine transporter imaging might be useful to rule out Parkinson's diseaseTreatmentOral medications:Modest in effectPropranolol: beta blocker that bests enters the CNS (metoprolol has little CNS penetrance)Primidone: makes you drowsy and sick; Others:TopiramateNeurontinMirtazapineBenzodiazepines: alprazolam is the most effective?Local therapyBotulinum toxinRare to use; better for a head tremor?Surgical therapy for severe tremorAblative proceduresDeep Brain StimulationVERY GOOD FOR THISParkinson diseaseEtiology and Course? Most common parkinsonian syndrome is the PD itself? Aka "the shaking palsy"? A chronic progressive neurodegenerative disorder causing motor impairment with cardinal features of: ? Resting tremor? Bradykinesia? Rigidity? Postural Instability? Highly variable presentation is the rule!Etiology?idiopathic?unclear role of mutations in parkin (PARK2) geneCourse?insidious onset, often initially affecting 1 limb and then spreading to others, asymmetric involvement usually persists?course will vary between persons, though chronic and progressive?slight male predominance, usually > 50 years old, 5% < 40 years old?tremor as presentation of Parkinson disease may predict more benign course and longer therapeutic response to levodopa Signs/ SymptomsMotorNon-MotorPOSTURAL CHANGESSPEECH CHANGES*DECREASED DEXTERITYHYPOMIMIAFESTINATING/FREEZING GAIT*DYSTONIAMICROGRAPHIADYSPHAGIA*CONSTIPATIONANOSMIAGERDDEPRESSION/ ANXIETYAPATHYCOGNITIVE CHANGESSLEEP DISTURBANCESSEBORRHEIC DERMATITISBLADDER URGENCY / FREQUENCYSWEATING SPELLSHYPOTENSIONSEXUAL DYSFUNCTIONPhysical FindingsGeneral physical: ?bradykinesia(2)?masking of facies(2)?speech may be(2)?quiet?stuttering?monotonous delivery without inflection?depression commonSkin: ?facial seborrheic dermatitisHEENT: ?decreased blink rate (giving sense of stare) may be one of earliest signsNeuro: ?resting tremor (Parkinsonian tremor) - "pill-rolling" tremor?frequency 4-6 Hertz?distal limbs, rhythmic?supination/pronation, finger flexion/extension or pill-rolling type?may present as inverted pattern, being more prominent in legs than arms especially in patients < 40 years?present at rest, may improve or disappear with purposeful function?observe when hands at rest?gait abnormalities(2)?difficulty initiating gait (freezing)?stooped posture (flexion of trunk and upper extremities)?tendency to fall forwards, or sideways, especially when turning?turning en bloc?may have shuffling with rapid propulsion?may have flexed posture of one arm with decrease in arm swinging when walking?examination for bradykinesia can include(2)?patient's tapping index finger and thumb?piano playing movements of fingers?foot tappingDiagnostic Testing?can be difficult to diagnose in early stages and diagnosis often delayed?diagnosis usually based on clinical findings and no further testing neededSupportive of PD ? Asymmetry ? Tremor in ONE hand, not both at same time for example? Insidious onset? Slow onset? UE > LE? initially? L-dopa response? Robust response for typical PD; but this is debatable?computed tomography and magnetic resonance imaging not helpful for diagnosis, but may help exclude other diagnoses, such as vascular disease and normal-pressure hydrocephalus?diagnostic testing for Parkinson disease?consider levodopa and apomorphine challenge for confirmation of Parkinson disease if diagnostic uncertainty ?consider olfaction testing to differentiate Parkinson disease from progressive supranuclear palsy and corticobasal degeneration, but not to differentiate Parkinson disease from multiple system atrophy TreatmentTotal treatment approach:? Cannot just rely on medicine!! Want to maintain quality of life: that is the goal. No medicine slows disease!!? What to Focus on:○ Medication○ Exercise§ Have Parkinson therapy that is specific. § Earlier started, the better the folks are. ○ Nutrition/Hydration○ Mood (good better, better the tremors)○ Sleep○ Activities (doing chore, social events, continue hobbies)Meds:LevodopaCarbidopa/ Levodopa (several formulations, IR, CR)Sinemet, Sinemet CR, Parcopa, in StalevoDrug of choice!Dopamine precursor (dopamine doesn’t cross BBB)Carbidopa prevents L-dopa from being broken down into peripheryStart low and titrate slowSE: N&V (ESPECIALLY NAUSEA), drowsiness, OH, Hallucinations,motor complications40% of patients develop motor complications w/i 5 years of levodopa tx (DATATOP study data, Ahlskog et al, Mov Dis 2001)Characteristics:Single wearing off timesEnd-of –dose wearing offDelayed-on / no-onUnpredictable off timesPeak-dose dyskinesia / dystoniaOff-dose dystonia / dyskinesiaDiphasic dyskinesiaRISK FACTORS FOR MOTOR COMPLICATIONS:YOUNGER AGE, EARLY L-DOPA EXPOSURE , HIGHER DOSE MORE QUICKLY, PULSATILE DOSINGSAME RISKS FOR DOPAMINE DYSREGULATION SYNDROME (DRIVE FOR HIGHER, MORE FREQUENT DOSES)Evolution of Motor Fluctuations-The therapeutic window for levodopa narrows with time; --that is, the duration of complication-free drug effect becomes more restricted over time. --This is believed to occur primarily because of the ongoing progression of the underlying disease.Peripheral causes of motor fluctuationDelayed gastric emptyingDietary protein competes for aa carriers in the gut that also transport L-dopaShort plasma half-lifeCentral causes of motor fluctuationpulsatile delivery to striatal receptorsalteration of DA receptors (through alteration in signal transduction that regulate gene expression)*impaired storage capacity from loss of dopaminergic neurons Dopamine AgonistsPramipexole (Mirapex)Ropinirole (Requip, Requip XLApomorphine (Apokyn – rescue therapy)Allow for much longer effect (none as robust as LDOPA)Do not alter pre-synaptic dopamineSE: N&V, hallucinations, OH, leg edema, Impulse Control Dis, Sleep attacksRisk of side effects for patients over 75 are HIGH (don’t use if old)RULE OF THUMB: if patient is "younger" (like under 70) you start them on this or another dopamine sparing agent)MAOB-ISelegeline (Eldepryl, Zelapar {Zydis form}Rasageline (Azilect)blocks dopamine breakdown enzymeNote: Selegeline breaks down in body to methamphetamine (don’t give late in day; no later than noon)Not used much anymore: use rasagelineSE: headache, OH or HTN, anxiety, insomniaCOMT-ITolcapone (Tasmar) Entacapone (Comtan, in Stalevo)Work in bloodstream to protect dopamine breakdownSE: GI (N, V & D), dopaminergic symptoms, urine discolorationAnti-CholinergicBenztropine (Cogentin)Trihexyphenidyl (Artane)Diphenhydramine (Benadryl)(first drugs, plant extracts)Really cause confusion and hallucination in elderly, but better in younger patients, especially those with prominent tremorSE: confusion / hallucinations, dry mouth, blurred vision, constipationAmantadine (Symmetryl)Anticholinergic, Antiglutamatergic (prevents neurotoxicity), dopamine release encouraged at nerve terminalCan be used to treat motor complications from levodopa therapy: ONLY DRUG TO DO THISSE: confusion / hallucinations, dry mouth, blurred vision, constipationSurgeryCandidatesTherapies○ Moderately Advanced PD○ Motor Fluctuations (respond best)○ Significant Disability despite Optimized Medications○ Response to Levodopa exists (respond best to DBS)○ Normal cognition (DBS can worsen cognition especially if baseline abnormality)○ Low surgical risk in general○ Ablation: permanent lesioningThalamotomyPallidotomy○ Deep Brain StimulationReversible, modifiable, implantation of electrodes into specific nucleiThalamus (Vim), Globus pallidus internus, Subthalamic nucleus (most common)Patient may still have infection, stroke, hemorrhage, death etc. but it is a good therapyProgram device that is within chest wall; adjust electrical current and maintain symptoms that way○ Transplantation / Restorative SurgeriesStill in the works.Follow-Up?annual review of Parkinson disease diagnosis - review all patients with a diagnosis of Parkinson disease at least annually including?current medications?presence of atypical features such as?falls at presentation and early in the disease course?poor response to levodopa?symmetry at onset?rapid progression [to Hoehn and Yahr stage 3 in 3 years]?lack of tremor?dysautonomia?assessment of psychiatric disorders or disturbances at least annually - all patients with a diagnosis of Parkinson disease assessed for psychiatric disorders or disturbances such as?psychosis?depression?anxiety disorder?apathy?impulse control disorder?assess all patients with a diagnosis of Parkinson disease for cognitive impairment or dysfunction at least annually?query about symptoms of autonomic dysfunction at least annually - ask all patients with a diagnosis of Parkinson disease (or caregivers, as appropriate) about symptoms of autonomic dysfunction including?orthostatic hypotension?constipation?urinary urgency/incontinence and fecal incontinence?urinary retention requiring catheterization?persistent erectile failure?query all patients with Parkinson disease (or caregivers, as appropriate) about sleep disturbances at least annually?query patients with Parkinson disease (or caregivers, as appropriate) about falls during all visits?Parkinson disease rehabilitative therapy options discussed at least annually with patient (or caregivers, as appropriate) including?physical therapy?occupational therapy?speech therapy?Parkinson disease–related safety issues counseling at least annually including?counsel all patients with a diagnosis of Parkinson disease (or caregivers, as appropriate) about context-specific safety issues appropriate to the patient’s stage of disease such as?injury prevention?medication management?driving?query for patients with a diagnosis of Parkinson disease (or caregivers, as appropriate) about Parkinson disease medication–related motor complications such as?wearing off?dyskinesia?or off-time?Parkinson disease medical and surgical treatment options reviewed with patients (or caregivers, as appropriate) at least once annually including?nonpharmacologic treatment?pharmacologic treatment?surgical treatmentHuntington diseaseEtiology and CourseEtiology? Trinucleotide repeat (CAG) disease? Normal repeat size < 36? Larger repeat = earlier onset? Autosomal Dominant inheritance? Every child has 50/50 chance. If you have the gene, you have the disease. ? Ch 4p16.3 encodes for huntingtin (htt)? Abnormal gene causes protein aggregation? Pathology seen in striatumCourse:? Progressive, fatal disease that causes motor and neuropsychiatric symptoms? Chorea, tics, gait disturbance? Psychosis, depression, anxiety, OCD? Advanced disease causes akinesia? Goes from hyperkinesia to AKINESIA? Dies from malnutrition or aspiration pneumonia? Unless they commit suicide : 11-15x greater than in regular population? Usually occurs in 30s-40s but can present at any age?median survival 15-20 years after onset of symptoms(1)?patients with late-onset disease may have more prolonged and benign course of illnessSigns/ Symptoms? Chorea: non-rhythmic, dance-like movements, that are brief but flow from part to part? Athetosis- nonrhythmic, slow writhing movements, often refers to hands or feet? Tics – suppressible, sudden, random, brief movements or vocalizations proceeded by a premonitory urge? Postural instability? Akinesia – lack of movement? Parkinsonism with progressive disease (rather than hyperkinetic)? Dystonic posturing (contracts, and stays contracts for a period of time)Physical FindingsSee aboveDiagnostic Testing?clinical diagnosis suspected if presence of?family history of Huntington disease?progressive motor abnormalities with chorea and possible impairment of fine motor skills?mental changes including cognitive decline, personality change, and/or depression?diagnosis confirmed by DNA analysis (≥ 36 CAG trinucleotide repeats in HTT gene)?36-39 CAG repeats - person at risk for Huntington disease, but may not develop symptoms?≥ 40 CAG repeats associated with development of Huntington disease?> 60 CAG repeats associated with juvenile onset (before age 20 years)?neuroimaging studies, such as magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT), and positron emission tomography (PET), may support clinical diagnosis of Huntington disease and may be used to monitor progression of disease?atrophy in caudate and putamen (striatum) may be seen prior to onset of symptomsTreatment? Limited treatment, no cure? Treatment: ? Antipsychotics, antidepressants, Sleep aids, ? For chorea (the abnormal movement) ?tetrabenazine (up to 100 mg/day)○ (dopamine depleting agent)○ Zenasine aka. ○ Associated with development or worsening of depression. ○ Used in some other disturbances like tics or tardive dyskinesia?amantadine (300-400 mg/day)?riluzole (200 mg/day)o MULTIPLE SCLEROSISEtiology and Course-Multiple Sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the brain and spinal cord (CNS) resulting in episodes of neurologic dysfunction that often recover (but degree of recovery can vary, may have gradually progressive course)?lesions can be disseminated in time and space (episodes affecting separate sites in the central system occurring at least 30 days apart)-Areas affected by MS○ Brain○ Spinal cord○ Optic nerves?clinically isolated syndrome (CIS) is an acute demyelinating episode affecting ≥ 1 site in CNSAntigen activates T-cell which activates pathway of multiple neurological changes.- Release of cytokines- Recruitment of lymphocytes and monocytes from periphery- Because of cytokines, the BBB is easier to disrupt- T cell can migrate into CNS- Once inside the CNS, get release of more inflammatory cytokines- Myelin is targeted- Demyelination and axonal transection are different○ Demyelination is recurrent○ Axonal involvement is progression of diseaseEtiology:?combination of genetic predisposition and environmental influence?increasing distance from equator generally correlates positively with higher incidence?migration from higher-risk area to lower-risk area in childhood associated with reduced risk?migration from lower-risk area to higher-risk area in childhood associated with increased riskPatternsRelapsing remitting (85%)?self-limited attacks of neurologic dysfunction with complete or partial recovery?acute onset, with evolution over days to weeks?most patients have variable degree of recovery over weeks to months?patient is neurologically and symptomatically stable between attacks(Goes back to baseline)Most commonIn terms of treatment, have the most medication for this areaSecondary progressive?begins as relapsing-remitting?patients develop progressive course later in disease with or without continued relapses?attack rate of relapses is usually reduced and course of illness is of steady deterioration in function?65% patients with relapsing-remitting enter secondary progressive phaseAs time goes one, goes back to baseline but have accompanying progression and baseline changes over time and you have disabilityPrimary progressive?steady decline in neurologic function without attacksFrom the get go, have progression of disabilityDon’t see the actual relapsesProgressive relapsing?begins as progressive course?patients may also experience occasional attacksHave progression from get go, but have attacks that go back to a progressive baseline?rarely seen, accounts for 1%-3% of multiple sclerosis populationLeast commonSigns /Symptoms?80% patients present with clinically isolated syndromesoptic neuritis (loss of visual acuity)?usually unilateral?typically painfulmyelitis (motor, sensory and/or sphincter problems)?partial sensory or motor dysfunction?sensory more common?Lhermitte sign may be seen in patients with cervical myelitis (electric sensation running down back or limbs with neck flexion)?commonly associated with bowel and bladder dysfunction?"band-like" abdominal or chest pressurebrainstem/cerebrum symptoms (double vision, facial pain, weakness and/or numbness)?ocular motor syndromes, such as internuclear ophthalmoplegia/nystagmus?hemisensory, crossed sensory syndromes?hemiparesis?trigeminal neuralgia?hemifacial spasmcerebellar symptoms (coordination problems)?cerebellar outflow tremor?acute ataxic syndromeother symptoms?tonic spasms?paroxysmal dysarthria/ataxia?Uhthoff phenomenon - transient worsening of vision or other neurologic symptoms with increased core temperature (such as during exercise, hot bath, fever)(2)?useless hand of Oppenheim - sensation that hand or arm is unusable despite no visible weakness or ataxia, likely due to sensory deafferentation?Pulfrich phenomenon - visual phenomenon where patients may perceive moving objects as having an anomalous pathwayPhysical FindingsHEENT: ?eye findings can include?decreased visual acuity?decreased color vision?scotoma (holes in visual field)?external ophthalmoplegia (eye movement disorders)?nystagmus?relative afferent pupillary defect?tested by swinging light between eyes?pupil of diseased optic nerve or retina enlarges when illuminated while healthy pupil constricts?may be seen with optic neuritis, other optic neuropathies, asymmetric glaucoma, and some retinal problems?other findings from brainstem lesions may include?dysarthria?impaired swallowingNeuro: ?upper motor neuron signs (including weakness, spasticity, hyperreflexia, Babinski sign) ?hemisensory loss?hemiparesis?tremor (can be postural and/or action tremor)?poor balance?clumsiness (limb incoordination and gait ataxia)?cognitive deficits?attention dysfunction?problems with executive function?dementia?emotional labilityDiagnostic TestingOverview?magnetic resonance imaging of brain and spinal cord with and without contrast?lumbar puncture for cerebrospinal fluid studies including?oligoclonal bands?immunoglobulin G (IgG) index?visual evoked potentials probably useful to identify patients at increased risk for developing clinically definite multiple sclerosisInternational diagnostic criteria for MS (2010 revisions to McDonald criteria) - any of?≥ 2 attacks with objective clinical evidence of ≥ 2 lesions, or objective clinical evidence of 1 lesion with reasonable historical evidence of prior attack?attack is defined as patient-reported or objectively observed event with?presentation typical of acute inflammatory demyelinating CNS event?duration ≥ 24 hours?absence of fever or infection?to make definite diagnosis of MS, at least 1 attack needs to be confirmed by neurologic exam, abnormal visual evoked potential response in patient reporting prior visual disturbance, or MRI consistent with demyelination in area corresponding to history of previous neurologic symptoms?≥ 2 attacks with objective clinical evidence of 1 lesion and dissemination in space demonstrated by ≥ 1 T2 lesion involving at least 2 of 4 typical CNS regions (periventricular, juxtacortical, infratentorial, or spinal cord)?gadolinium enhancement of lesions not required?if patient has brainstem or spinal cord syndromes, symptomatic lesions are not included for consideration of meeting criteria?1 attack with objective clinical evidence of ≥ 2 lesions and dissemination in time demonstrated by any of?asymptomatic gadolinium-enhancing and non-enhancing lesions occurring simultaneously at any time?new T2 and/or gadolinium-enhancing lesion on follow-up MRI (regardless of timing in comparison to baseline scan)?1 attack with objective clinical evidence of only 1 lesion (clinically isolated syndrome) and both dissemination in space and time as noted aboveOther- Absence of other treatable causes for the symptomsTreatmentMeds:For Clinically Isolated Syndrome?interferon betareduces risk for developing clinically definite MS?glatiramer acetate (Copaxone)might delay onset of clinically definite MSFor Acute Exacerbation of MS?corticosteroidsmethylprednisolone -500-1,000 mg/day IV or --500-2,000 mg/day PO for 3-5 daysimprove symptoms and disability during acute exacerbationsPreventative1st Line?interferon beta interferon beta-1a (low dose) Avonex 30 mcg/wk IM(high dose) Rebif22 mcg or 44 mcg TIW SCIndications: CIS, RRMSmultiple serious adverse effects including depression, suicide, hepatotoxicity, and injection site necrosisinterferon beta-1b (high dose) Betaseron, Extavia250 mcg QOD SC?glatiramer acetate (Copaxone)20 mg/d SCIndications: CIS, RRMS?appears as effective as interferon beta, and associated with fewer flu-like symptoms and injection site reactions2nd LineMonoclonal antibodies?natalizumab (Tysabri) 300 mg q4wk IVIndications: Relapsing forms of MSreduces relapse rate and progression of disability in patients with relapsing-remitting MS but use limited by association with progressive multifocal leukoencephalopathy?alemtuzumab (Campath)may be more effective than interferon beta-1a in patients with early, relapsing-remitting MS, but also associated with autoimmune adverse eventsOthers?cladribine (Leustatin) reduces relapse rate in relapsing-remitting MS not FDA approved for use in MSfingolimod (Gilenya)reduces relapse rate and disease progression in relapsing-remitting MS fingolimod reduces relapse rate more than interferon beta-1aSphingosine-1P (S-1P) receptor agonist; Blocks lymphocyte migrationdimethyl fumarate (Tecfidera)may decrease risk of relapse in patients with relapsing-remitting MS3rd LineMitoxantrone12 mg/m2 over 5–15 min q3mo IV infusionIndications: SPMS, PRMS, Worsening RRMSSymptom Based TxSpasticityNonpharmacologic treatments should be used prior to pharmacologic treatments? Physical therapy} Exercises (stretching and range of motion)} Aquatic exercises are popular; critical that water temperature be approximately 85oF (warmer temperatures cause fatigue; colder temperatures exacerbate spasticity)? Mechanical aids} Orthotics} BracesPharmacological txinitial treatment should be baclofen or gabapentinOral baclofen is the drug of choiceAdverse events (AEs) include somnolence and confusionAEs decrease over time (taper slowly)Avoid suddenly stopping the drug: Seizures, hallucinations, and death can resultIntrathecal baclofen may be given was wellWalking Speeddalfampridine (Ampyra) extended-release tablets FDA approved to improve walking speed in patients with MSPain?treat sharp, shooting neuropathic pain or painful hypersensitivity with:anticonvulsants (such as carbamazepine or gabapentin) or antidepressants (such as amitriptyline) ?nortriptyline and transcutaneous electrical nerve stimulation (TENS) appear to have similar efficacy for reducing pain and/or sensory complaints in upper extremitiesFatigueMultidisciplinary:– Fatigue resulting from extreme spasticity may be lessened by stretching exercises and/or antispasm medications– Fatigue resulting from an infection requires treatment of the underlying condition– Fatigue arising from a mood disorder may respond best to combination therapy with medications and counseling– Fatigue arising from lifestyle factors (ie, overexertion) may respond to teaching patients to not overexert themselvesPharmacologicalModafinil (Provigil)100–400 mg once daily in the AMFirst-line agent for improving daytime fatiguecan reduce the efficacy of hormonal contraception!!Remind women of childbearing age who use oral contraceptives to use back-up contraceptionArmodafinil50-250 mg once daily in the morningAmantadine100 mg twice daily (AM and in the early afternoon)may provide small clinical benefitUrinary ProblemsFailure to store (hyperreflexive bladder)The most common bladder problem seen in MS patientsTx: Anticholinergic medications (eg, oxybutynin, tolterodine)1,2Most common adverse effects (AEs)—dry mouth and constipationAEs more common with immediate-release formulationsRemind patients to increase fluid intakeAdherence very important with sustained-release formulations?patients with nocturia desmopressin 100-400 mcg orally or 10-40 mcg intranasally at nightTremor?botulinum toxin type A associated with improvement in upper extremity tremor severity in patients with MS Pseudobulbar affect?dextromethorphan 20 mg/quinidine sulfate 10 mg (Nuedexta) FDA approved for treatment of pseudobulbar affect in patients with MS, and may reduce frequency and severity of pseudobulbar affect episodes ?other treatments to consider are tricyclic antidepressant (NICE Grade B) selective serotonin reuptake inhibitor VASCULAR DISORDERS____________________________________________________________________________________Intracranial aneurysmEtiology and CourseSaccular aneurysms (“berry” aneurysms)usually congenital result from developmental weakness of the vessel wall, especially at sites of branchingoccur at arterial bifurcations, most at anterior part of the circle of Willis—particularly on the anterior or posterior communicating arteries, at the bifurcation of the middle cerebral artery, and at the bifurcation of the internal carotid artery.are frequently multiple (20% of cases), usually asymptomatic. may be associated with: polycystic kidney disease coarctation of the aorta. Risk factors for aneurysm formation include:smoking, hypertension, hypercholesterolemia. Mycotic aneurysmsMycotic aneurysmsresulting from septic embolismoccur in more distal vessels and often at the cortical surfaceCourse:typically asymptomaticcomplication of intracranial aneurysms is a subarachnoid hemorrhageSigns/Symptomsmost are asymptomatic produce only nonspecific symptoms until they rupture, at which time subarachnoid hemorrhage results.Physical FindingsDiagnostic TestingDefinitive evaluation is by angiography (bilateral carotid and vertebral studies), generally indicates the size and site of the lesion, sometimes reveals multiple aneurysms, may show arterial spasm if rupture has occurred. Visualization by CT or MR angiography is not usually adequate if operative treatment is under consideration because lesions may be multiple and small lesions are sometimes missedTreatmentSymptomatic but unruptured aneurysms, merit prompt treatment, either surgically or by endovascular techniques, Small asymptomatic ones discovered incidentally often monitored arteriographically corrected only if they increase in size to over 10 mm.? StrokeIschemic StrokeEtiology and CourseEtiologyAtherothrombotic cerebrovascular (20%)Intracranial vessels : same thing that causes MICardioembolic (20%)Clot forms in heart, then goes to heart○ Valve○ Atrial septal defect○ Afib Lacunar (25%):small vessel diseaseCryptogenic (30%)We don’t know what causes these ones!May be Paroxysmal Afib○ The afib that comes and goes! Especially in elderly patients○ Afib incidence increases with ageOther (5%)Vasospasm, etc CourseStrokes begin abruptly.Neurologic deficits may be maximal at onset, as is common in embolic stroke, or may progress over seconds to hours (or occasionally days), which may occur with progressive arterial thrombosis or recurrent emboli.Stroke-in-evolution, or progressing stroke, causes deficits that continue to worsen even as the patient is seen. Completed stroke is defined by the presence of persistent deficits, which may be stable or improving when the patient is seenSigns/ Symptomsocclusion of a blood vessel interrupts the flow of blood to a specific region of the brain, interfering with neurologic functions dependent on that region and producing a more or less stereotyped pattern of deficits- Sudden numbness or weakness of the face, arm or leg, especially on one side of the body- Sudden trouble seeing in one or both eyes- Sudden confusion, trouble speaking or understanding- Sudden trouble walking, dizziness (talking about vertigo: illusion of moving), loss of balance or coordination- Sudden severe headache with no known causeAnterior circulation? anterior cerebral artery○ frontal lobe affected-cognitive impairment○ contralateral weakness, numbness, dysarthria? middle cerebral artery○ contralateral paralysis (arm/face > LE)○ *classic findings (facial drooping, etc.)Posterior circulation? varied presentation, can have LOC, impaired visionPhysical FindingsDiagnostic Testing?In all patients, immediate studies for evaluation of suspected acute ischemic stroke (AHA/ASA Class I, Level B)?neuroimaging?used to confirm diagnosis and distinguish between intracerebral hemorrhage and ischemic stroke?most appropriate imaging studies are computerized tomography (CT) without contrast, or magnetic resonance imaging (MRI)?other?blood glucose?serum electrolytes and renal function tests?electrocardiogram (ECG) - baseline ECG recommended, but should not delay IV tissue plasminogen activator (t-PA) (AHA/ASA Class I, Level B)?markers of cardiac ischemia - baseline troponin level recommended but should not delay IV t-PA (AHA/ASA Class I, Level C)?complete blood count, including platelet count?prothrombin time/INR?activated partial thromboplastin time?oxygen saturationTreatmentMainstay for ischemic stroke is TPA if indicated. For acute ischemic stroke, only treat bp if significantly elevated. Exception is if fibrinolysis is indicated (onset < 3 hours) then you can use simple measures to lower bp below 185/110. Labetalol, nicardipine infusion.?Blood pressure controlif SBP > 220 or DBP > 130If no tPA, we don't really careIf we are giving tPA, try to control it?Fibrinolytic therapyIV tPA (tissue plasminogen activator): helps breakdown clots?if used, alteplase (t-PA, rt-PA, Activase) dose 0.9 mg/kg (maximum 90 mg) IV (10% over 1 minute, 90% over 1 hour)within 3 hours of onset of ISCHEMIC stroke symptomsMust have a deficit (not just facial numbness)up to 3-4.5 hours in certain populationsInclusionexclusion> 18 yoclinical dx of ischemic stroke with measurable deficittime of onset well established < 180 min before administration of tPAexcludes patient who wake up with stroke symptomsevidence of intracranial hemorrhageminor or rapidly resolving symptomshigh clinical susp of subarachnoid hemorrhageactive internal bleeding (GI, urinary) within 21 daysbleeding diathesis (based on patients personal hx of bleeding or potential to bleed)platelets < 100,000elevated PTT and heparin useelevated PT and warfarin usewithin 3 mo of intracranial surgery, serious head trauma or strokewithin 14 days of major surgery or serious traumarecent arterial puncture at noncompressible sitelumbar puncture within 7 dayshx of intracranial hemorrhage, AV malformation or aneurysmwitnessed seizure at stroke onsetrecent AMIrepeated elevated BP (>185/110) requiring aggressive treatment to maintain at that level?Additional Exclusion Criteria For treating between 3-4.5 hours:>80 yoNIHSS score > 25Hx of diabetes mellitusBlood glucose <50 or >400?So basically you don’t want to give tPA to someone who is getting better, or who is a bleeder, who recently bled or who has the potential to bleed somewhere that would be bad or that would be hard to control. Elev BP + tPA = risk for bleeding?Other options:Intra-arterial thrombolysisintraarterial-up to 6 hoursMechanical clot removalMERCI-corkscrew device that pulls clot out-up to 8 hours?Often do both therapies, tPA and the others.Anti-platelet/Anti-coagulation?aspirin 160-325 mg once daily?recommended starting 24-48 hours after stroke in most patients to reduce risk of death, dependency, and recurrent stroke ?NOT recommended within first 24 hours of IV fibrinolysis and may increase risk of symptomatic intracranial hemorrhage ?anticoagulation?multiple guidelines recommend against anticoagulation in acute ischemic stroke for reducing morbidity, mortality, or recurrent stroke Follow-Up?observe for neurologic deterioration within first 24 hours?monitor cardiac rhythm for at least first 24 hours to screen for arrhythmiasHemorrhagic StrokeEtiology and CourseIntracerebral hemorrhage (70%)Here blood is bathing the brain○ Most due to chronic HTN, but there are other reasons: coagulopathies (congenital or drug induced), congenital malformation: AV malformationSubarachnoid (30%)Traumatic cause: most common○ Most common non-traumatic: ruptured aneurysm Common sites of aneurysmSigns/Symptomsless predictable pattern of focal involvement because complications such as increased intracranial pressure, cerebral edema, compression of brain tissue and blood vessels, or dispersion of blood through the subarachnoid space or cerebral ventricles can impair brain function at sites remote from the hemorrhageIntracerebral hemorrhage S/Sheadache, staggering gait, diplopia, nausea, vomiting, vertigo, blurred vision, neurologic deficits; rarely seizures, stuporPhysicalGeneral? coma?quadriplegia and coma with hemorrhage in pons?look for signs of increased intracranial pressure - bradycardia, decreased respiratory rate, third nerve palsy?localizing signs ?putamen - both eyes deviate conjugately to side of lesion, contralateral hemiplegia, hemisensory defect?thalamus - both eyes deviate downward and medially, impairment of vertical eye movements, pupils small (0.5-2 mm) and nonreactive (sluggishly reactive), contralateral hemisensory loss, lethargy, more visual field cut if lateral geniculate nucleus involved?pons - both eyes in mid-position, no doll's eye movements, pinpoint (< 1 mm) pupils but reactive (use magnifying glass, essentially non-reactive otherwise), coma common, flaccid quadriplegia?cerebellum - inability to stand or walk, vertigo, dysarthriaHEENT: ?pupillary abnormalitiesNeuro: ?focal signs on examination dependent on site of hemorrhagetends to cause more severe headache and depression of consciousness as well as neurologic deficits that do not correspond to the distribution of any single blood vessel.Subarachnoid hemorrhageS/S?sudden onset of severe headache, often described as "worst headache ever" or "thunderclap" headache?nausea?vomiting?neck pain?photophobia?loss of consciousnessPhysicalGeneral physical: ?altered level of consciousnessHEENT: ?retinal hemorrhages?with aneurysmal hemorrhage, preretinal hemorrhages may predict Terson's syndrome (occurrence of a vitreous hemorrhage), indicating more abrupt increase in intracranial pressure and increased mortalityNeck: ?meningismus, nuchal rigidityNeuro: ?focal neurological signs most commonly include?partial or complete III nerve palsy (posterior communicating artery aneurysm)?VI nerve palsy (due to increased intracranial pressure)?bilateral leg weakness (anterior communicating aneurysm)?abulia (anterior communicating aneurysm)?hemiparesis with aphasia or visuospatial neglect (middle cerebral artery aneurysm)Physical FindingsDiagnostic Testing?CT without contrastshows increased density, shift of intracranial contents, compression of ventricles?lumbar puncture if high index of suspicion and neuroimaging unremarkableTreatment? ABC’s? More likely to be obtunded? Some of these patients will need to be intubated. ? Blood pressure control? Idea is that elevated bp will worsen bleeding, so control it to less than 160 systolic-nicardipine, labetalol, esmolol.? CTA? If in subarachnoid space? May coil an aneurysm? Evacuate clot? Place shunt in ventricles ?oral nimodipine 60 mg every 4 hours recommended for aneurysmal subarachnoid hemorrhage? Anticoagulation reversal? IV vitamin K, Fresh frozen plasma, PCC (prothrombin complex concentrate)? Many of these patients will be on coumadin, so we reverse that with certain agents. ? Neurosurgery, interventional neuroradiology consult? Intervention depends on location and type of bleed. Often they will evacuate the clot, they can put in a VP shunt for bleeding in the ventricles.? ICU admissionTIAEtiology and Course?transient episode of neurologic dysfunction caused by focal ischemia of brain, spinal cord, or retina, and without acute infarction on neuroimaging?specific time-based definition controversialmost TIAs are brief< 1 hour in 60%< 2 hours in 71%> 6 hours in 14%Etiologycardiogenic emboli?atrial fibrillation?sick sinus syndrome?cardiomyopathy?mitral stenosis?mitral regurgitation?post-myocardial infarction (ventricular wall aneurysm, mural thrombus)?prosthetic heart valve thrombosis?infective endocarditis?nonbacterial thrombotic endocarditis?calcific aortic stenosis?calcification of mitral annulus?atrial myxoma?intracardiac defects with paradoxical embolism (patent foramen ovale, atrial septal defect (ASD), Eisenmenger syndrome)carotid or vertebral artery disease?atherosclerotic large vessel disease - carotid artery stenosis, vertebral artery stenosis and occlusion?artery-to-artery embolism?anterograde extension of embolus into cerebral arteries?arterial dissection?fibromuscular dysplasia?thoracic aortic aneurysm and dissection?arteritis - Takayasu arteritis, temporal arteritis?granulomatous angiitis?vasculopathy from drug abuse?arteriolar spasmhematologic disorders?increased sludging (polycythemia vera, sickle cell disease, erythrocytosis)?decreased cerebral oxygenation (severe anemia)?thrombocytosis?thrombocytopenia?leukemias with white blood cell count > 150,000 cells/mcL?hyperviscosity?thrombophilia (protein C or S deficiency, lupus anticoagulant, antithrombin III deficiency, plasminogen deficiency)Signs/SymptomsAnterior Circulation(carotid, middle cerebral artery, anterior cerebral artery),Posterior Circulation(vertebrobasilar circulation),?motor dysfunction of contralateral extremities, face, or both including?weakness?clumsiness?paralysis?loss of vision in ipsilateral eye (transient monocular blindness, amaurosis fugax)?homonymous hemianopia?speech disturbances?aphasia (if involvement of dominant hemisphere)?dysarthria (can be from motor involvement of either dominant or nondominant hemisphere)?sensory deficit of contralateral extremities, face, or both?numbness or sensory loss?cortical sensory loss (extinction of sensation, agnosias)?motor dysfunction of ipsilateral face and/or contralateral extremities (crossed pattern) including?weakness?clumsiness?paralysis?loss of vision of 1 or both homonymous visual fields (including cortical blindness and Anton's syndrome [lack of awareness of blindness])?sensory deficit of ipsilateral face and/or contralateral extremities (crossed pattern)?paresthesias?numbness or sensory loss?other focal neurologic findings with posterior circulation includes associated signs and symptoms often occurring in patterns together?ataxia of gait, trunk, extremities?vertigo (with other associated neurologic findings)?diplopia?dysarthria?dysphagiaPhysical FindingsHEENT: ?check for emboli (including cholesterol, marantic, or blood) on funduscopic examNeck: ?check for carotid and supraclavicular bruitsCardiac: ?evaluate for arrhythmia (such as atrial fibrillation) and murmursNeuro: ?careful exam looking for evidence of focal neurologic deficits which should resolveDiagnostic Testing?diagnosis based on?transient episode of neurological dysfunction ?absence of acute infarction found on neuroimaging, preferably magnetic resonance imaging including diffusion-weighted sequences?neuroimaging?patients with TIA should have neuroimaging within 24 hours of symptom onset ?magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), is preferred brain imaging modality?head computed tomography (CT) should be done if MRI not available?imaging studies determine classification of event (such as stroke or TIA, hemorrhage)?routine blood tests for evaluation of patients with suspected TIA include complete blood count looking for evidence of polycythemia?chemistry panel?blood glucose to rule out hypoglycemia?prothrombin time/partial thromboplastin time to rule out coagulopathy?fasting lipid panel to assess for risk of atherosclerotic vascular diseaseTreatment?inpatient vs. outpatient management?reasonable to hospitalize patients with TIA if presenting within 72 hours of event and ABCD2 score ≥ 3, unclear if outpatient workup can be completed within 2 days, or suspected focal ischemia ?if not admitting patient to hospital, same-day evaluation for TIA or minor stroke associated with reduced risk of recurrent stroke at 90 days ?aspirin 160-325 mg/day recommended within 48 hours of TIA ?for prevention of stroke after TIA, risk factor reduction strategies include?moderate physical activity for ≥ 30 minutes 1-3 times/week ?statin therapy to target low-density lipoprotein (LDL) cholesterol < 100 mg/dL or < 70 mg/dL statins reduce subsequent cerebrovascular events in adults with history of stroke or transient ischemic attack (TIA) ?blood pressure reduction, including diuretics and/or angiotensin-converting enzyme (ACE) inhibitors ?smoking cessation ?avoiding heavy alcohol use Assessing risk of stroke after a TIA: ABCD2 ScoreCriteriaScoreAge > 60 yo (1)BP > 140/90 (1)Clinical featuresUnilateral weakness (2)Speech impairment without weakness (1)Duration Symptoms 10-59 minutes (1)Symptoms > 60 minutes (2)Diabetes (1)0-3=low risk (1% risk of stroke in 48 hrs)4-5=moderate risk (4.1% risk of stroke in 48 hrs)6 or greater=high risk (8% risk of stroke in 48 hrs)SEIZURE DISORDERS______________________________________________________________________________________SeizureClassificationPartial Focal origin: One localization of brainFurther subdivide based on level of consciousnessSimpleNo loss of consciousnessMay go into complex partial seizureWith motor signs( Jacksonian , versive, and postural)Jacksonian- March: starts in extremity, marches up the arm (one part stops, another starts)?With sensory symptoms( visual, somatosensory, olfactory, auditory, gustatory, and vertiginous)?With psychic symptoms( dysphasia, dysmensic, hallucinatory, and affective changes)?With autonomic symptoms( epigastric sensation, pallor, flushing, pupillary changes)ComplexLoss of consciousness (consciousness is impaired)May go into generalized seizureSimple partial onset followed by impaired consciousnessWith impairment of consciousness at onsetWith automatismBoth types of partial seizures can spread, resulting in secondarily generalized tonic-clonic seizures.Aka secondary generalized seizureElectrical charges diffuse into other areas of the brain?Note:A Partial seizures manifest themselves in many different forms, depending on which area of the cortex is involved in the onset and spread of the ictal dischargeAn aura often reflects the location of the seizure-onset zoneEpilepsia partialis continua, a continuous focal motor seizure that remains confined to a specific body part and usually consists of clonic movements that can persist for up to months with preserved consciousnessEPC: very difficult to treat; psychogenic originGeneralizedDiffuse or bilateral originNon-focalConvulsive or non-convulsiveTypically have loss of consciousness?CharacteristicsGeneralized seizures are those in which the first clinical changes indicate that both hemispheres are initially involved. Consciousness usually is impaired during generalized seizures, although some seizures, such as the myoclonic type, may be so brief that impairment of consciousness cannot be assessed. ?Types:Absence seizures: not a seizure for an adult (teens, children)May be confused with ADD as patient "daydreams"May happen several times in a given periodAbnormal EEG finding: 3 per second spike and wave Myoclonic seizuresBrief extremity seizureTonic-clonic seizuresAka grand malClonic is jerking motionTonic seizuresStiffnessAtonic seizuresSeizure without any movement at allEtiology and Course?seizure is abnormal electrical brain activity (with or without clinical motor manifestations○ Epilepsy usually is defined as two or more recurring seizures not directly provoked by intracranial infection, drug withdrawal, acute metabolic changes, or fever.Etiology:Toxic metabolic1. Systemic illness2. Drugs and toxins3. Withdrawal syndromes4. Pyridoxine deficiencyAcquired Structural Lesion1. Infection2. Vascular3. Trauma4. Neoplasms and other lesions5. Mesial temporal sclerosis6. Other. ? Alzheimer's disease, Creutzfeldt—Jakob's disease, and in rare instances, multiple sclerosis.FamilialOthergenetic syndromes associated with seizuresDrugs lowering seizure threshold?antipsychotics?chlorpromazine and clozapine have highest risk of seizures?haloperidol, risperidone, and olanzapine have lowest risk?antidepressants?bupropion (Wellbutrin) has highest risk?tricyclic antidepressants (TCAs) can lower seizure threshold?selective serotonin reuptake inhibitors (SSRIs) preferred for at-risk patients?antihistamines (older drugs, for example diphenhydramine) may induce seizures?analgesics ?meperidine (Demerol) produces neurotoxic metabolite which can accumulate with chronic use?tramadol (Ultram) can cause seizures?for some antibiotics, seizures can occur with high IV doses or doses not adjusted for renal function?fluoroquinolones?cephalosporins?penicillins?carbapenems?bowel preparations?sodium phosphate can cause seizures due to electrolyte imbalance?polyethylene glycol safer for at-risk patients?drug withdrawal with?benzodiazepines?barbiturates?opiates?baclofenCourseIn epilepsy:seizures occur unpredictably at any time and without any relationship to posture or ongoing activities. Occasionally, however, they occur at a particular time (eg, during sleep) or in relation to external precipitants such as lack of sleep, missed meals, emotional stress, menstruation, alcohol ingestion (or alcohol withdrawal; see below), or use of certain drugs. Fever and nonspecific infections may also precipitate seizures in epileptic patientsSigns/SymptomsBefore/During SeizureAfter Seizure?aura?autonomic changes including ?change in heart rate?change in respiratory rate?dilated pupils?incontinence?drooling?pallor?vomiting?behavior change?preictal symptoms?loss of consciousness or inability to speak?motor manifestations including posturing, clonic (jerking) movements, tonic posture (stiffening)?vocal symptoms?cry or gasp?slurring of words?garbled speech?respiratory symptoms?change in breathing pattern?cessation of breathing?cyanosis?amnesia for events?bitten tongue, especially lateral borders?confusion?lethargy?headache and muscle aches?nausea and vomiting?sleepiness?transient focal weakness (Todd paralysis)FAVORING EVENTS:Epileptic seizuresPsychogenic non-epileptic seizuresAuraBrief duration (1 to 2 minutes)Postictal confusionAbnormal posturingAmnesia for the eventIncontinenceEvents arising from sleepSelf-injury (lateral tongue biting)Eyes open at the onset of the eventSpecific nontraditional triggers (triggers other than photic stimulation or hyperventilation)Event occurs in the waiting room or examination roomHistrionic behavior during the examinationRapid cognitive postictal recoveryAbility to induce a seizurePresence of fibromyalgia, chronic painPhysical FindingsTongue/extremity ictal injuries?signs of ongoing seizure such as nonconvulsive status epilepticus?altered mental status?new focal neurologic signsDiagnostic TestingFirst Seizure?For all patients:?brain imaging using either computerized tomography (CT) or magnetic resonance imaging (MRI) ?electroencephalogram (EEG) ?laboratory tests which may be helpful for specific clinical circumstances but insufficient evidence to support or refute recommendation for routine use (AAN Level U)(1)?blood tests?blood counts?blood glucose?electrolytes (especially sodium)?toxicology screening?lumbar punctureTreatment?initial evaluation after seizure should include determination of?normalization of vital signs?adequate oxygenation?cessation of seizure activity?benzodiazepines recommended for seizure cessation if seizures are prolonged (≥ 5 minutes) or repeated?IV lorazepam 4 mg (may repeat after 5-10 minutes) preferred if IV access already established and resuscitation facilities available?rectal diazepam appears effective for acute repetitive seizures, but associated with somnolence ?antiepileptic drug therapy for seizure disorder usually started after second epileptic seizure, or after first unprovoked seizure if:?neurologic deficit?definite epileptic activity on EEG?risk of further seizures considered unacceptable?structural abnormality on neuroimaging(For AED specifics, see appendix)Follow-Upregular laboratory monitoring for all AEDRefer to Neurologyo CEREBRAL PALSYGroup of conditions that are characterized by chronic movement or posture abnormalities that are cerebral in origin, arise early in life, and are nonprogressiveSignificant mental retardation, defined as an intelligence quotient (IQ) of less than 50, is associated with 25 percent of cerebral palsy cases.Cerebral palsy is commonly classified by the type of neurological dysfunction—spastic, dyskinetic, or ataxic—as well as the number and distribution of limbs involved—quadriplegia, diplegia, hemiplegia, or monoplegia. The major types and their frequencies are: ?Spastic quadriplegia, which has a strong association with mental retardation and seizure disorders—20 percent?Diplegia, which is common in preterm or low-birthweight infants—30 percent?Hemiplegia—30 percent?Choreoathetoid types—15 percent?Mixed varietiesEtiology and Course?70% unknown, 20% can be correlated with risk factors, occasionally specific causes (embryologic malformations and infection)##Brain tissue that may not develop correctly during pregnancy—growing fetus may experience a lack of oxygen or nutrients##Child sustains a head injury or brain infection##Mother and child's blood types are not compatible##Mother has rubella while pregnant##Stroke or bleeding occurs in the baby's brain during development or after birth ##Child does not get enough oxygen during or after birth##There are abnormalities of the umbilical cord or placenta, or the placenta separates too early from the wall of the uterus## Child has meningitis, encephalitis, seizures, or head injury ##Child has genetic/metabolic abnormalities?perinatal asphyxia extremely rare as cause of cerebral palsyCourse:CP first shows up in children aged three years or younger. Symptoms vary depending on what areas of the brain are affected. Some children may have severe disabilities. Although symptoms may change as the child grows older, the child's condition is unlikely to worsen.Signs/Symptoms?history of nonprogressive motor delay, usually mental retardation, 2/3 seizures##Late to turn over, sit up, smile, or walk##Trouble writing, buttoning a button, or other fine motor activities##Difficulty walking or standing##Tight, spastic muscles##Weak muscles##Poor balance##Speech problems##Tremors##Unintentional body movements##Difficulty swallowing##DroolingPhysical FindingsNeuro: findings consistent with CNS lesion and commonly include: ?hyperactive reflexes?abnormal movements of chorea, athetosis, or dystonia?spasticity?ataxia?abnormal absence or persistence of infantile reflexes (Moro, asymmetrical tonic neck, parachute)(damage must be permanent for diagnosis)Diagnostic Testing?metabolic screening for inherited disorders, which are the most common cause of progressive neurologic disorders?difficult to distinguish from progressive neurologic disorder earlyRule out: ?idiopathic toe-walking ?Pelizaeus-Merzbacher disease (slowly progressive X-linked disorder, begins in infancy, resembles cerebral palsy but progressive)?MRI at near term may identify premature infants who will develop cerebral palsy ?MRI at near term more sensitive than serial cranial ultrasounds in first 2 weeks for predicting cerebral palsyTreatmentmuscle strength training might improve gait in adolescents and adults with cerebral palsyhippotherapy or therapeutic horseback riding might improve postural balance and control in children with cerebral palsy? Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy:?for localized/segmental spasticity warranting treatment (AAN Level A)?botulinum toxin type A should be offered as effective and generally safe treatment?insufficient data to support or refute use of phenol, alcohol, or botulinum toxin type B (AAN Level U)?for generalized spasticity warranting treatment?diazepam should be considered for short-term treatment, with caution regarding toxicity (AAN Level B)?tizanidine may be consideredThere is no treatment to cure CP. The brain damage cannot be corrected. Therapy aims to help the child reach his or her full potential. Children with CP grow to adulthood and may be able to work and live independently.MedicationDrugs help control muscle spasms and seizures.##Glycopyrrolate—to decrease drooling## Pamidronate—to treat osteoporosis## Medicines that may be used to treat spasticity: ##Botulinum toxin##Baclofen##Diazepam##TizanidineSurgeryCertain operations may improve the ability to sit, stand, and walk.?selective posterior rhizotomy may be helpful for refractory spasticity; procedure includes ?laminectomy?separation of sensory nerve roots from motor nerve roots?microscopic separation of sensory nerve roots into rootlets?stimulation of sensory nerve rootlets to determine which ones to obliterate?comprehensive rehabilitation program?electrical stimulation may be usefulPhysical Aids Braces and splints help keep limbs in correct alignment and prevent deformities. Positioning devices enable better posture. Walkers, special scooters, and wheelchairs make it easier to move around.Follow-UpConsultation and referral: ?orthopedics if lower extremity involvement (braces, special shoes, tendon releases, tendon transfers, joint stabilizations)APPENDIXMigraine TherapyDrugRoute1StrengthRecommended DoseCommentsA. Acute (Abortive) TreatmentSimple analgesicsAspirinPO325 mg650 mg q4hMay cause gastric pain or bleeding and rebound headache if used frequently.Naproxen sodiumPO250, 375, 500 mg500–1,000 mg at onset, then 250–500 prn after 1 hourIbuprofenPO200, 400, 600, 800 mg800-1,200 mg at onset, then 600-800 mg q4–8hKetoprofenPO25, 50, 75, 100, 150, 200 mg75-150 mg q6hAcetaminophenPOPR325, 500 mg650-1,000 mg at onset, then q4hAcetaminophen/isometheptene/dichloralphenazone is marketed as Midrin.(If analgesics ineffective, switch to triptans for next headache.)TriptansSumatriptanNS20 mg/spray20 mgMay repeat once after 2 hours for partial response. May cause nausea and vomiting; contraindicated by pregnancy, coronary or peripheral vascular disease, concurrent treatment with monoamine oxidase inhibitors, and hemiplegic or basilar migraine.PO25, 50, 100 mg50-100 mgSC6 mg6 mgRizatriptanPO5, 10 mg10 mgZolmitriptanPO2.5, 5 mg2.5-5 mgNS5 mg/spray5 mgAlmotriptanPO6.25, 12.5 mg6.25-12.5 mgEletriptanPO20, 40 mg40 mgFrovatriptanPO2.5 mg2.5 mgNaratriptanPO1, 2.5 mg2.5 mgErgot alkaloidsErgotamine/caffeine (Cafergot)PR2 mg/100 mg1/4-2 suppositories, up to 5 per weekMay cause nausea and vomiting; contraindicated in pregnancy and coronary or peripheral vascular disease.Dihydroergotamine (DHE)NS0.5 mg/spray1 spray to each nostril, up to 5 times per weekRepeat after 15 minutes. May cause nausea and vomiting; contraindicated in pregnancy and coronary or peripheral vascular disease.SC1 mg/mL1-2 mgRepeat 1 mg q12h, up to 6 mgIV0.75-1.25 mg IVNarcotic analgesicsCodeine/aspirinPO15, 30, 60/325 mg30-120 mg codeineMeperidinePOIM50, 100 mg50-200 mgButorphanolNS10 mg/mL (1 mg/spray)1 spray every 3-4 hours as neededB. Prophylactic TreatmentAnti-inflammatory agentsAspirinPO325 mg325 mg qodMay cause gastric pain or bleedingNaproxen sodiumPO275, 550 mg550-825 mg bidTricyclic antidepressantsAmitriptylinePO10, 25, 50, 75, 100, 150 mg10-300 mg hsMay cause dry mouth or urinary retention. Begin with lowest dose and increase slowly. Adding an anticonvulsant may increase efficacy.NortriptylinePO10, 25, 50, 75 mg10-150 mg hsDesipraminePO10, 25, 50, 75, 100 mg25-300 mg qhsβ-Receptor antagonistsPropranololPO10, 20, 40, 60, 80, 90 mg20-120 mg bidListed in descending order of efficacy. Symptomatic bradycardia may occur at high doses. Contraindicated in asthma and congestive heart failure and in patients on calcium channel blockers. To discontinue, taper over 1-2 weeks.PO (long acting)60, 80, 120, 160 mg60-320 mg qdNadololPO40, 80, 120, 160 mg40-240 mg qdAtenololPO50, 100 mg50-200 mg qdTimololPO10, 20 mg10-30 mg qdMetoprololPO50, 100 mg100-200 mg qdAnticonvulsantsPhenytoinPO100 mg200-400 mg qdValproic acidPO125, 250, 500 mg; 500 mg extended release250-1,000 mg bid or in single dose with extended releaseBegin with lowest dose. Contraindicated in iramatePO15, 25, 100, 200 mg25-200 mg qdStart 25 mg hs and increase by 25 mg/d every 7 days as tolerated.GabapentinPO100, 300, 400, 600, 800 mg900-2,400 mg qdLess effective than other anticonvulsants.Calcium channel antagonistsVerapamilPO40, 80, 120 mg80-160 mg tidContraindicated by severe left ventricular dysfunction, hypotension, sick sinus syndrome without artificial pacemaker, second- or third-degree AV nodal block, and in patients on β-blockers. Constipation is most common side effect. Verapamil ineffective in migraine without aura.FlunarizinePO (long acting)240 mg240 mg qd-bidPO5, 10 mg5-15 mg/dayOther agentsRiboflavin (vitamin B2)2POVarious400 mg/dOnabotulinum toxin AIM100 units/vial100-250 unitsUseful in chronic migraine. Injected into head and neck muscles.C. AntiemeticsProchlorperazinePO5, 10, 15 mg25 mg q6hPR2.5, 5, 25 mg25 mg q12hIM, IV5 mg/mL10 mg (with 10 mg diphenhydramine)Adjunctive treatment to reduce nausea and improve enteric absorption of antimigraine drugs. May cause dystonia, which responds to 10 mg IV diphenhydramine.ChlorpromazineIM25 mg/mL50 mgIV25 mg/mL0.1 mg/kg drip over 20 minutesPromethazinePO, PR12.5, 25, 50 mg25-50 mg q6hMetoclopramidePO5, 10 mg5-20 mg tidAEDS: DrugUsual Adult Daily Oral DoseMinimum No. of Daily DosesTime to Steady-State Drug LevelsOptimal Drug LevelSelected Side Effects and Idiosyncratic ReactionsGeneralized or focal seizuresPhenytoin200–400 mg15–10 days10–20 mcg/mLNystagmus, ataxia, dysarthria, sedation, confusion, gingival hyperplasia, hirsutism, megaloblastic anemia, blood dyscrasias, skin rashes, fever, systemic lupus erythematosus, lymphadenopathy, peripheral neuropathy, dyskinesias.Carbamazepine extended-release (ER) formulation400–1600 mg ER23–4 days4–8 mcg/mLNystagmus, dysarthria, diplopia, ataxia, drowsiness, nausea, blood dyscrasias, hepatotoxicity, hyponatremia. May exacerbate myoclonic seizures.Valproic acid 1500–2000 mg2–32–4 days50–100 mcg/mLNausea, vomiting, diarrhea, drowsiness, alopecia, weight gain, hepatotoxicity, thrombocytopenia, tremor, pancreatitis.Phenobarbital100–200 mg114–21 days10–40 mcg/mLDrowsiness, nystagmus, ataxia, skin rashes, learning difficulties, hyperactivity.Primidone750–1500 mg34–7 days5–15 mcg/mLSedation, nystagmus, ataxia, vertigo, nausea, skin rashes, megaloblastic anemia, irritability.Lamotrigine1,2,5100–500 mg 24–5 days?Sedation, skin rash, visual disturbances, dyspepsia, iramate1–4200–400 mg24 days?Somnolence, nausea, dyspepsia, irritability, dizziness, ataxia, nystagmus, diplopia, glaucoma, renal calculi, weight loss, hypohidrosis, hyperthermia.Oxcarbazepine1,3900–1800 mg22–3 days?As for carbamazepine.Levetiracetam1,21000–3000 mg22 days?Somnolence, ataxia, headache, behavioral changes.Zonisamide1200–600 mg114 days?Somnolence, ataxia, anorexia, nausea, vomiting, rash, confusion, renal calculi. Do not use in patients with sulfonamide allergy.Tiagabine132–56 mg22 days?Somnolence, anxiety, dizziness, poor concentration, tremor, diarrhea.Pregabalin1150–300 mg22–4 days?Somnolence, dizziness, poor concentration, weight gain, thrombocytopenia, skin rashes, anaphylactoid reactions.Gabapentin1900–3600 mg31 day?Sedation, fatigue, ataxia, nystagmus, weight loss.Felbamate1,3,61200–3600 mg34–5 days?Anorexia, nausea, vomiting, headache, insomnia, weight loss, dizziness, hepatotoxicity, aplastic anemia.Lacosamide1100–400 mg23 days?Vertigo, diplopia, nausea, headache, fatigue, ataxia, tremor, anaphylactoid reactions, PR prolongation, cardiac dysrhythmia, suicidalityEzogabine1300–1200 mg32–3 days?Dizziness, somnolence, confusion, vertigo, nausea, ataxia, psychiatric disturbancesVigabatrin1,23000 mg22 days?Somnolence, anorexia, nausea, vomiting, agitation, hostility, confusion, suicidality, neutropenia, Stevens-Johnson syndromeAbsence seizuresEthosuximide100–1500 mg25–10 days40–100 mcg/mLNausea, vomiting, anorexia, headache, lethargy, unsteadiness, blood dyscrasias, systemic lupus erythematosus, urticaria, pruritus.Valproic acid 1500–2000 mg32–4 days50–100 mcg/mLSee above.Clonazepam0.04–0.2 mg/kg2?20–80 ng/mLDrowsiness, ataxia, irritability, behavioral changes, exacerbation of tonic-clonic seizures.Myoclonic seizuresValproic acid 1500–2000 mg32–4 days50–100 mcg/mLSee above.Clonazepam0.04–0.2 mg/kg2?20–80 ng/mLSee above.1Approved as adjunctive therapy for focal-onset seizures.2Approved as adjunctive therapy for primary generalized tonic-clonic seizures.3Approved as initial monotherapy for focal-onset seizures.4Approved as initial monotherapy for primary generalized tonic-clonic seizures.5Approved as monotherapy (after conversion from another drug) in focal-onset seizures.6Not to be used as a first-line drug; when used, blood counts should be performed regularly (every 2–4 weeks). Should be used only in selected patients because of risk of aplastic anemia and hepatic failure. It is advisable to obtain written informed consent before use.Bottom of Form ................
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