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Session 4

  1. 1. Conditions of the Neurological System Part A: Module A2 Session 4
  2. 2. Objectives <ul><li>Describe the various etiological agents that cause neurological disorders </li></ul><ul><li>Give key points when taking a history </li></ul><ul><li>Describe the clinical presentation of each disorder </li></ul><ul><li>List the recommended diagnostics and common findings for each disorder </li></ul><ul><li>Understand the treatment and management of neurological disorders </li></ul><ul><li>Discuss preventive measures </li></ul><ul><li>Make a differential diagnosis using a case study approach </li></ul>
  3. 3. Overview <ul><li>Reported incidence of neurological abnormalities on clinical examination varies greatly, from 16% to 72% among hospitalized patients </li></ul><ul><li>A wide range of neurological manifestations is reported: cognitive defects, focal deficits such as hemiplegia and acute peripheral facial palsy, painful feet syndrome, encephalopathy </li></ul><ul><li>Some of these manifestations are directly caused by HIV itself, others are the result of OIs caused by different pathogens or drugs </li></ul>
  4. 4. Major Pathogens <ul><li>Protozoal infection Toxoplasma Gondii (toxoplasmosis) </li></ul><ul><li>Mycobacterial infection M. tuberculosis (TB meningitis) </li></ul><ul><li>Bacterial Strep pneumoniae, </li></ul><ul><li>Neisseria meningitis (bacterial meningitis) </li></ul><ul><li>Fungal infection Cryptococcus neoformans </li></ul><ul><li>(cryptococcal meningitis) </li></ul><ul><li>Viral infection Cytomegalovirus (CMV) </li></ul><ul><li>Other : Progressive multifocal leukoencephalopathy (PML) </li></ul><ul><ul><li>Primary CNS lymphoma </li></ul></ul><ul><ul><ul><li>  HIV-associated dementia (HAD) </li></ul></ul></ul><ul><ul><ul><li>Painful sensory and motor peripheral neuropathies </li></ul></ul></ul><ul><ul><ul><li>Neurosyphilis </li></ul></ul></ul>
  5. 5. Chart 2. Conditions of the Neurological System Other - Primary CNS lymphoma - HIV-associated dementia (HAD) - painful sensory and motor peripheral neuropathies - neurosyphilis Protozoal Infection Toxoplasma Gondi (toxoplasmosis) <ul><li>Viral Infection </li></ul><ul><li>- Cytomegalovirus (CMV) </li></ul><ul><li>- Progressive multifocal </li></ul><ul><li>leukoencephalopathy (PML) </li></ul>Fungal Infection Cryptococcus neoformans (cryptococcal meningitis) Bacterial Infection Strep pneumoniae, Neisseria meningitis(Bacterial meningitis Mycobacterial infection - M. tuberculosis (TB meningitis) Unique features/caveats Management and Treatment Diagnostics (lab & x-ray) Signs and symptoms Pathogen
  6. 6. Protozoal infection: Toxoplasma Gondii (toxoplasmosis) Presenting Signs and Symptoms <ul><li>Clinical symptoms may evolve </li></ul><ul><ul><li>Focal neurological deficits, e.g., seizures, hemiparesis, hemiplegia, cerebellar tremor, cranial nerve palsies, hemisensory loss, visual problems or blindness, personality changes, cognitive disorders </li></ul></ul><ul><ul><li>Headache (severe, localized) </li></ul></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Confusion </li></ul></ul><ul><ul><li>Myalgia </li></ul></ul><ul><ul><li>Arthralgia </li></ul></ul>
  7. 7. <ul><li>CSF values </li></ul><ul><ul><li>Normal: 20-30% </li></ul></ul><ul><ul><li>Protein: 10-150/ml </li></ul></ul><ul><ul><li>WBC: 0-40 (monos) </li></ul></ul><ul><ul><li>Blood: FBC </li></ul></ul><ul><ul><li>***** </li></ul></ul><ul><li>An HIV-infected individual presenting with typical signs and symptoms and normal cerebrospinal fluid findings should be put on treatment for toxoplasmosis </li></ul>Diagnostics
  8. 8. Cerebral t oxoplasmos is
  9. 9. Management and Treatment <ul><li>Provide physiotherapy as necessary </li></ul><ul><li>Start anti-convulsant treatment </li></ul><ul><ul><li>Epanutin 50 – 100 mg bid or tid or tegretol 100 – 200 mg bid or tid (to be started only if the patient has convulsion) </li></ul></ul>
  10. 10. Management and Treatment, continued <ul><li>Start Treatment for acute phase: </li></ul><ul><ul><li>Pyrimethamine 100 – 200 mg loading dose, then 50 – 100 mg/day po + folinic ( or folic) acid 10 mg/day po + sulfadiazine 1-2g qid for at least 6 weeks </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>Trimethoprim/Sulfamethoxazole (10/50mg/kg daily) for 4 weeks </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>Clindamycin (600mg tid) + pyrimethamine 100mg daily loading dose followed by 50 mg daily + folinic acid 10 mg daily </li></ul></ul>
  11. 11. Unique features, Caveats <ul><li>One of the most common HIV-related neurological complications </li></ul><ul><li>If patient does not receive maintenance therapy, disease will recur. Usually occurs when CD4<100 </li></ul><ul><li>Check blood picture regularly as relatively high doses of drugs can lead to toxicities </li></ul><ul><li>Leukopenia thrombocytopenia and rash are common. Folinic acid reduces the risk of myelosuppression </li></ul><ul><li>During treatment, patients should maintain a high fluid intake and urine output </li></ul><ul><li>Preventive measures and prophylaxis: See Part One, Module 2/Session 10 </li></ul>
  12. 12. Treatment after a case of Toxo <ul><li>Preferred regimen for suppressive therapy required after a patient has had Toxo: </li></ul><ul><ul><li>Pyrimethamine 25-75 mg po qd + folinic acid 10 mg qd + sulfadiazide 0.5-1.0 gm po qid </li></ul></ul><ul><ul><li>If allergic to sulfa </li></ul></ul><ul><ul><li>Give Dapsone po 100 mg po once daily or Clindamycin IV (or oral) 600 mg qid or Atovaquine 750 mg po qid </li></ul></ul>
  13. 13. Mycobacterial Infection: M. tuberculosis (TB Meningitis) Presenting Signs and Symptoms <ul><li>Gradual onset of headache and decreased consciousness </li></ul><ul><ul><li>Low grade evening fevers </li></ul></ul><ul><ul><li>Night sweats </li></ul></ul><ul><ul><li>Weight loss </li></ul></ul><ul><ul><li>Neck stiffness and positive Kernig’s sign </li></ul></ul><ul><ul><li>Cranial nerve palsies result from exudate around base of the brain </li></ul></ul>
  14. 14. <ul><li>CSF Values </li></ul><ul><ul><li>Normal: 5-10% </li></ul></ul><ul><ul><li>Protein: High (40mg/dl-100 mg/dl) </li></ul></ul><ul><ul><li>WBC: 5-2000 (average is 60-70% monos) </li></ul></ul><ul><ul><li>Glucose: low (<20 mg/dl) </li></ul></ul><ul><ul><li>AFB smear pos: 20% </li></ul></ul>Diagnostics
  15. 15. Unique features, Caveats <ul><li>CD4<350 </li></ul><ul><li>Up to 10% of HIV/AIDS patients who present with TB will show involvement of the meninges. This results either from the rupture of a cerebral tuberculoma or it is blood-borne </li></ul><ul><li>Always exclude cryptococcal meningitis by CSF microscopy (India ink stain) </li></ul>
  16. 16. Bacterial Infection: Strep pneumoniae, Neisseria Meningitis (Bacterial Meningitis) Presenting Signs and Symptoms <ul><li>Symptoms tend to present within one week of infection. May be preceded by a prodromal respiratory illness or sore throat. </li></ul><ul><ul><ul><li>- Fever - Vomiting </li></ul></ul></ul><ul><ul><ul><li>- Headache - Malaise </li></ul></ul></ul><ul><ul><ul><li>- Stiff neck - Irritability </li></ul></ul></ul><ul><ul><ul><li>- Photophobia - Drowsiness </li></ul></ul></ul><ul><ul><ul><li>- Coma </li></ul></ul></ul>
  17. 17. <ul><li>CSF Values </li></ul><ul><ul><li>leukocytosis </li></ul></ul><ul><ul><li>cerebrospinal fluid shows increased pressure </li></ul></ul><ul><ul><li>cell count (100 –10,000/mm 3 ) </li></ul></ul><ul><ul><li>protein (>100 mg/dl) </li></ul></ul><ul><ul><li>decreased glucose (<40 mg/dl or <50% of the simultaneous glucose blood level) </li></ul></ul><ul><ul><li>gram-stained smear of the spun sediment of the CSF can reveal the etiologic agent </li></ul></ul>Diagnostics
  18. 18. Management and Treatment <ul><li>Penicillin (24 million units daily in divided doses every 2-3 hours) </li></ul><ul><li>or </li></ul><ul><li>Ampicillin (12 gr daily in divided doses every 2-3 hours) </li></ul><ul><li>or </li></ul><ul><li>Chloramphenicol (4 to 6 grams IV/day). Treatment should be continued for 10 to 14 days. </li></ul><ul><li>Crystalline penicillin 2-3 mega units and chloramphenicol 500-750 mg every 6 hours for 10-14 days </li></ul>
  19. 19. Unique features, Caveats <ul><li>Often encountered during late stages of HIV disease. Prompt diagnosis and aggressive management and treatment ensure a quick recovery </li></ul>
  20. 20. Fungal Infection: Cryptococcus neoformans   (cryptococcal meningitis) Presenting Signs and Symptoms <ul><li>Presentation usually nonspecific at onset. This may be true for > 1 month. </li></ul><ul><ul><li>Protracted headache and fever may be the only signs </li></ul></ul><ul><ul><li>Nausea, vomiting, and stiff neck may be absent and focal neurological signs uncommon. </li></ul></ul><ul><ul><li>Extraneural symptoms: </li></ul></ul><ul><ul><ul><li>- skin lesions, pneumonitis, pleural effusions and retinitis </li></ul></ul></ul><ul><ul><li>Fever, malaise, nuchal pain signify a worse prognosis, and nausea and vomiting and altered mental status in terminal stages </li></ul></ul>
  21. 21. <ul><li>CSF Values </li></ul><ul><ul><li>Normal 20% </li></ul></ul><ul><ul><li>Protein 30-150/dl </li></ul></ul><ul><ul><li>WBC: 0-100 (monos) </li></ul></ul><ul><ul><li>Glucose decreased: 50-70mg/dl </li></ul></ul><ul><ul><li>Culture positive: 95-100% </li></ul></ul><ul><ul><li>India ink positive: 60-80% </li></ul></ul><ul><ul><li>Crypt Ag nearly 100% sensitive and specific </li></ul></ul>Diagnostics
  22. 22. Cryptoccoc al meningitis: CSF I ndian ink examination
  23. 23. Management and Treatment <ul><li>Preferred regimen: </li></ul><ul><ul><li>Amphotericin P 0.7 mg/kg/day IV, + flucytosine 100 mg/kg/day po x 14 days, followed by Fluconazole 400 mg/day x 8-10 weeks. Finally, maintenance therapy with Fluconazole 200mg/day for life </li></ul></ul>
  24. 24. Management and Treatment, continued <ul><li>Alternate regimen: </li></ul><ul><ul><li>Amphotericin B 0.7 mg/kg/day IV + flucytosine 100mg/kg/day po x 14 days followed by itraconazole 200mg bid for 8 weeks </li></ul></ul><ul><ul><li>Fluconazole 400 mg/day po x 8 weeks followed by 200 mg once daily </li></ul></ul><ul><ul><li>Itraconazole 200 mg po tid x 3days, then 200 mg po bid x 8 weeks after initial treatment with amphotericin </li></ul></ul><ul><ul><li>Fluconazole 400 mg/day po + flucytosine 100 mg/kg/day po </li></ul></ul>
  25. 25. Unique features, Caveats <ul><li>If untreated, it is slowly progressive and ultimately fatal </li></ul><ul><li>Most common life-threatening fungal infection in HIV/AIDS patients. Also the most common cause of meningitis in patients with HIV/AIDS in Africa and Asia. Occurs most often in patients with CD4<50 </li></ul><ul><li>It is better prevented than treated </li></ul>
  26. 26. Unique features, Caveats, continued <ul><li>Headache is secondary to fungal accumulation. Headache increases gradually over time and then follows a recurring pattern. It becomes harder to get rid of, and then becomes continuous. This is what the patient reports. </li></ul><ul><li>Requires lifelong suppressive treatment unless immune reconstitution occurs </li></ul>
  27. 27. Viral Infection: Cytomegalovirus (CMV) Presenting Signs and Symptoms <ul><li>Fever  delirium, lethargy, disorientation, malaise, headache most common </li></ul><ul><li>Stiff neck, photophobia, cranial nerve deficits less common </li></ul><ul><li>No focal neurological deficits </li></ul><ul><li>Gastrointestinal symptoms: diarrhea, colitis, esophageal ulceration appear in 12-15% of patients </li></ul><ul><li>Respiratory symptoms, i.e, pneumonitis, present ~1% </li></ul>
  28. 28. <ul><li>Retinal exam to check for changes. Consult an ophthalmologist </li></ul><ul><li>CMV retinitis, characterized by creamy yellow white, hemorrhagic, full thickness retinal opacification, which can cause visual loss and lead to blindness if untreated; patient may be asymptomatic or complain of floaters, diminished acuity or visual field defects. Retinal detachment if disease is extensive </li></ul><ul><li>UGI endoscopy when indicated </li></ul>Diagnostics
  29. 30. Management and Treatment <ul><li>Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h x 14-21 days; ganciclovir 5mg/kg IV bid x 14-21 days. Patients without immune recovery will need to be on maintenance therapy lifelong for retinitis </li></ul><ul><li>Extra-ocular; ganciclovir and/or foscarnet </li></ul>
  30. 31. Unique features, caveats <ul><li>Evolution occurs in less than 2 weeks </li></ul><ul><li>Usually when CD4<100 </li></ul><ul><li>  </li></ul><ul><li>Although any part of the retina may be involved, there is a predilection for the posterior pole; involvement of the optic nerve head and macula region is common </li></ul><ul><li>Characteristically involves the retinal vessels which are always abnormal in areas involved by retinitis. There is minimal or no accompanying uveitis </li></ul><ul><li>  </li></ul><ul><li>Rare but devastating illness in resource poor settings. Treatment is very expensive and usually not available. CMV management needs special care. Therefore, early referral is essential </li></ul>
  31. 32. Viral Infection: Progressive mul ltifocal leukoencephalopathy (PML) Presenting Signs and Symptoms <ul><li>Afebrile, alert, no headache </li></ul><ul><li>Progressively impaired speech, vision, motor function </li></ul><ul><li>Cranial nerve deficit and cortical blindness </li></ul><ul><li>Cognition affected relatively late </li></ul>
  32. 33. <ul><li>CT brain scan may be normal or remarkable for areas of diminished density or demyelination (deterioration of the covering of the nerve) </li></ul><ul><li>PCR of CSF for detection of JC virus </li></ul><ul><li>JC virus PCR is positive in about 60% of the cases </li></ul><ul><li>Differential diagnosis: </li></ul><ul><ul><ul><li>Toxoplasmosis </li></ul></ul></ul><ul><ul><ul><li>Primary CNS lymphoma </li></ul></ul></ul><ul><li>  </li></ul><ul><li>Definitive diagnosis is by brain biopsy (if available) </li></ul>Diagnostics
  33. 34. Management and Treatment <ul><li>There is no treatment for this illness </li></ul><ul><li>ART can improve symptoms and prolong life </li></ul>
  34. 35. Unique features, Caveats <ul><li>An end-stage complication of HIV, caused by the JC virus </li></ul><ul><li>  </li></ul><ul><li>PML is rare in the general community, but relatively common in HIV infection (affecting 4% of all AIDS patients). Routine testing for HIV should be considered for any patient with PML </li></ul><ul><li>  </li></ul><ul><li>Evolution occurs over weeks to months </li></ul><ul><li>CD4<100 </li></ul>
  35. 36. Primary CNS lymphoma Presenting Signs and Symptoms <ul><li>Disease progresses slowly over a few weeks </li></ul><ul><li>Afebrile </li></ul><ul><li>Headache </li></ul><ul><li>Focal and multifocal neuro deficits (confusion, hemiplegia, seizures) </li></ul><ul><li>Mental status change (60%), personality or behavioral </li></ul><ul><li>Seizures (15%) </li></ul>
  36. 37. Cerebral lymphoma
  37. 38. <ul><li>CT Scan/MRI </li></ul><ul><li>Location: pre-ventricular in one or more site </li></ul><ul><li>Prominent edema, irregular and solid on enhancement. </li></ul><ul><li>  </li></ul><ul><li>CSF: </li></ul><ul><ul><li>Normal;—30-50% </li></ul></ul><ul><ul><li>Protein—10-150/ml </li></ul></ul><ul><ul><li>WBC—0-100 (monos) </li></ul></ul><ul><ul><li>Cytology positive in <5% </li></ul></ul><ul><ul><li>Suspect with negative toxo IgG or failure to respond to empiric toxo treatment </li></ul></ul>Diagnostics
  38. 39. Management and Treatment <ul><li>There is no cytotoxic chemotherapy for this disease. Irradiation can help some patients, but is considered palliative  </li></ul><ul><li>Corticosteroids can also help some patients </li></ul>
  39. 40. Unique features, Caveats <ul><li>Primary CNS Lymphoma is RARE in the general community, but affects about 2% of AIDS patients </li></ul><ul><li>Survival after diagnosis is usually limited (a few months only) </li></ul><ul><li>Typical end-stage complication of HIV disease </li></ul><ul><li>Evolution: 2-8 weeks </li></ul><ul><li>Usually occurs when CD4<100 </li></ul>
  40. 41. HIV-associated dementia (HAD) Presenting Signs and Symptoms <ul><li>In up to 10% of patients it is the first manifestation of HIV disease </li></ul><ul><li>Afebrile; general lethargy </li></ul><ul><li>Triad of cognitive, motor and behavioral dysfunction </li></ul><ul><li>Early - concentration and memory deficits, inattention, motor-uncoordination, ataxia, depression, emotional lability </li></ul><ul><li>Late - global dementia, paraplegia, mutism </li></ul>
  41. 42. <ul><li>Neuropsychological tests show subcortical dementia </li></ul><ul><li>Mini-mental exams not very sensitive </li></ul>Diagnostics
  42. 43. AIDS dementia complex
  43. 44. Management and Treatment <ul><li>Possible benefit from ARV agents that penetrate the CNS (AZT, d4T, ABC, nevirapine) </li></ul><ul><li>Benefit of AZT at higher dose for mild or moderately severe cases is established; monitor therapy with neurocognitive tests </li></ul><ul><li>Anecdotal experience indicates response to ART if started early </li></ul>
  44. 45. Management and Treatment, continued <ul><li>Sedation for those who are agitated and aggressive—use smaller doses initially to avoid over-sedation </li></ul><ul><li>Close monitoring: to prevent self-harm, ensure adequate nutrition, diagnose and treat OIs early </li></ul><ul><li>Psychological support for caregivers—exhausting work; caregivers need regular breaks and may need counseling </li></ul>
  45. 46. Painful Sensory and Motor Peripheral Neuropathies <ul><li>Presenting signs and symptoms </li></ul><ul><li>Burning pain and numbness in toes and feet, ankles, calves, fingers in more advanced cases </li></ul><ul><li>Paraplegia </li></ul><ul><li>Autonomic dysfunction </li></ul><ul><li>Poor bowel/bladder control </li></ul><ul><li>Dizziness secondary to postural hypotension </li></ul><ul><li>Contact hypersensitivity in some cases </li></ul><ul><li>Mild/moderate muscle tenderness </li></ul><ul><li>Muscle weakness </li></ul><ul><li>Later: Reduced pinprick/vibratory sensation; reduced or absent ankle/knee jerks </li></ul><ul><li>Sweating </li></ul>
  46. 47. <ul><li>Electromyography/nerve conduction velocities show predominantly axonal neuropathy </li></ul><ul><li>CPK usually elevated </li></ul><ul><li>CSF - look for cytomegalovirus or herpes simplex virus infections—lymphomatous infiltration </li></ul><ul><li>Spinal fluid to determine etiology </li></ul><ul><li>Serum B12 and TSH </li></ul><ul><li>Quantitative sensory testing or thermal thresholds may be helpful </li></ul>Diagnostics
  47. 48. Management and Treatment <ul><li>Exclude neurotoxic drugs, alcoholism, diabetes, B12 deficiency, thyroid problems and treat underlying causes if known. </li></ul><ul><li>Discontinue presumed neurotoxic medication </li></ul><ul><li>Provide proper nutrition and vitamin supplements </li></ul>
  48. 49. Management and Treatment, continnued <ul><li>Pain control: </li></ul><ul><ul><li>Ibuprofen 600-800 mg po tid or codeine for modest symptoms </li></ul></ul><ul><ul><li>Amitryptiline 25-50 mg at night </li></ul></ul><ul><ul><li>Phenytoin 50-100 mg bid or carbamazapine 100-200 mg tid– especially for episodic shooting pain. May have to combine antidepressants with anti-convulsants </li></ul></ul><ul><ul><li>Methadone or morphine for severe symptoms </li></ul></ul><ul><ul><li>Lidocaine 10-30% ointment for topical use </li></ul></ul><ul><li>Physical therapy may be helpful, but may be hampered by pain </li></ul><ul><li>Nutrition counseling and psychological support </li></ul>
  49. 50. Unique features, Caveats <ul><li>Differential: toxoplasmosis, primary CNS lymphoma  </li></ul><ul><li>Management and treatment is difficult. </li></ul><ul><li>Consider physical therapy combined with pain management. </li></ul>
  50. 51. Neurosyphilis Presenting Signs and Symptoms <ul><li>Can be asymptomatic </li></ul><ul><li>Headache, fever, photophobia, meningismus  seizures, focal findings, cranial nerve palsies </li></ul><ul><li>Tabes dorsalis —sharp pains, parasthesias, decreased DTRs, loss of pupil response </li></ul><ul><li>General paresis— memory loss, dementia, personality changes, loss of pupil response </li></ul><ul><li>Meningovascular strokes, myelitis </li></ul><ul><li>Ocular syphilis—iritis, uveitis, optic neuritis </li></ul>
  51. 52. <ul><li>CT Scan/MRI: Aseptic meningitis—may show meningeal enhancement. General paresis—cortical atrophy, sometimes with infarcts. Meningovascular syphilis—deep strokes. May present like dementia. </li></ul><ul><li>CSF: Protein—45-200/ml </li></ul><ul><li>WBCs—5-100 (monos) </li></ul><ul><li>VDRL positive—sensitivity 65%; specificity 100% positive </li></ul><ul><li>Serum VDRL and FTA-ABS are clue in >90%; false neg serum VDRL in 5-10% with tabes dorsalis or general paresis </li></ul><ul><li>Definitive diagnosis: positive CSF, VDRL (found in 60-70%) </li></ul>Diagnostics
  52. 53. Management and Treatment <ul><li>Give Aq penicillin G, 18-24 mil units/day x 10-14 days </li></ul><ul><li>Follow-up VDRL every 6 months until negative </li></ul><ul><li>  Indications to re-treat: </li></ul><ul><ul><li>CSF WBC fails to decrease at 6 months or CSF still abnormal at 2 years </li></ul></ul><ul><ul><li>Persisting signs and symptoms of inflammatory response at 3 months </li></ul></ul><ul><ul><li>Four-fold increase in CSF VDRL at 6 months </li></ul></ul><ul><li>Failure of CSF VDRL of 1:16 to decrease by two-fold by 2 months or four-fold by 12 months </li></ul>
  53. 54. Unique features, Caveats <ul><li>RARE : affects only 0.5% of all HIV/AIDS patients </li></ul><ul><li>Most common forms in HIV-infected persons are ocular, meningeal, and meningovascular </li></ul><ul><li>Some evidence that syphilis progresses more rapidly in the context of HIV infection, so that complications such as meningovascular syphilis may occur at an unusually early phase. </li></ul><ul><li>  </li></ul>
  54. 55. Unique features, Caveats, continued <ul><li>Recommended that syphilis testing be offered to all clients presenting for VCT in high prevalence areas because it is treatable in early stages, and has an accelerated course in HIV. </li></ul><ul><li>CD4<350 </li></ul>
  55. 56. Thank You