Objectives

2. Objectives Describe the various etiological agents that cause neurological disorders Give key points when taking a history Describe the clinical presentation of each disorder List the recommended diagnostics and common findings for each disorder Understand the treatment and management of neurological disorders Discuss preventive measures Make a differential diagnosis using a case study approach

3. Overview Reported incidence of neurological abnormalities on clinical examination varies greatly, from 16% to 72% among hospitalized patients A wide range of neurological manifestations is reported: cognitive defects, focal deficits such as hemiplegia and acute peripheral facial palsy, painful feet syndrome, encephalopathy Some of these manifestations are directly caused by HIV itself, others are the result of OIs caused by different pathogens or drugs

4. Major Pathogens Protozoal infection Toxoplasma Gondii (toxoplasmosis) Mycobacterial infection M. tuberculosis (TB meningitis) Bacterial Strep pneumoniae, Neisseria meningitis (bacterial meningitis) Fungal infection Cryptococcus neoformans (cryptococcal meningitis) Viral infection Cytomegalovirus (CMV) Other: Progressive multifocal leukoencephalopathy (PML) Primary CNS lymphoma � HIV-associated dementia (HAD) Painful sensory and motor peripheral neuropathies Neurosyphilis

6. Protozoal infection: Toxoplasma Gondii (toxoplasmosis)Presenting Signs and Symptoms Clinical symptoms may evolve Focal neurological deficits, e.g., seizures, hemiparesis, hemiplegia, cerebellar tremor, cranial nerve palsies, hemisensory loss, visual problems or blindness, personality changes, cognitive disorders Headache (severe, localized) Fever Confusion Myalgia Arthralgia

7. CSF values Normal: 20-30% Protein: 10-150/ml WBC: 0-40 (monos) Blood: FBC ***** An HIV-infected individual presenting with typical signs and symptoms and normal cerebrospinal fluid findings should be put on treatment for toxoplasmosis Diagnostics

9. Management and Treatment Provide physiotherapy as necessary Start anti-convulsant treatment Epanutin 50 � 100 mg bid or tid or tegretol 100 � 200 mg bid or tid (to be started only if the patient has convulsion)

10. Management and Treatment, continued Start Treatment for acute phase: 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 or Trimethoprim/Sulfamethoxazole (10/50mg/kg daily) for 4 weeks or Clindamycin (600mg tid) + pyrimethamine 100mg daily loading dose followed by 50 mg daily + folinic acid 10 mg daily

11. Unique features, Caveats One of the most common HIV-related neurological complications If patient does not receive maintenance therapy, disease will recur. Usually occurs when CD4<100 Check blood picture regularly as relatively high doses of drugs can lead to toxicities Leukopenia thrombocytopenia and rash are common. Folinic acid reduces the risk of myelosuppression During treatment, patients should maintain a high fluid intake and urine output Preventive measures and prophylaxis: See Part One, Module 2/Session 10

12. Treatment after a case of Toxo Preferred regimen for suppressive therapy required after a patient has had Toxo: Pyrimethamine 25-75 mg po qd + folinic acid 10 mg qd + sulfadiazide 0.5-1.0 gm po qid If allergic to sulfa Give Dapsone po 100 mg po once daily or Clindamycin IV (or oral) 600 mg qid or Atovaquine 750 mg po qid

13. Mycobacterial Infection: M. tuberculosis (TB Meningitis) Presenting Signs and Symptoms Gradual onset of headache and decreased consciousness Low grade evening fevers Night sweats Weight loss Neck stiffness and positive Kernig�s sign Cranial nerve palsies result from exudate around base of the brain

14. CSF Values Normal: 5-10% Protein: High (40mg/dl-100 mg/dl) WBC: 5-2000 (average is 60-70% monos) Glucose: low (<20 mg/dl) AFB smear pos: 20% Diagnostics

15. Unique features, Caveats CD4<350 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 Always exclude cryptococcal meningitis by CSF microscopy (India ink stain)

16. Bacterial Infection: Strep pneumoniae, Neisseria Meningitis (Bacterial Meningitis) Presenting Signs and Symptoms Symptoms tend to present within one week of infection. May be preceded by a prodromal respiratory illness or sore throat. - Fever - Vomiting - Headache - Malaise - Stiff neck - Irritability - Photophobia - Drowsiness - Coma

17. CSF Values leukocytosis cerebrospinal fluid shows increased pressure cell count (100 �10,000/mm3) protein (>100 mg/dl) decreased glucose (<40 mg/dl or <50% of the simultaneous glucose blood level) gram-stained smear of the spun sediment of the CSF can reveal the etiologic agent Diagnostics

18. Management and Treatment Penicillin (24 million units daily in divided doses every 2-3 hours) or Ampicillin (12 gr daily in divided doses every 2-3 hours) or Chloramphenicol (4 to 6 grams IV/day). Treatment should be continued for 10 to 14 days. Crystalline penicillin 2-3 mega units and chloramphenicol 500-750 mg every 6 hours for 10-14 days

19. Unique features, Caveats Often encountered during late stages of HIV disease. Prompt diagnosis and aggressive management and treatment ensure a quick recovery

20. Fungal Infection: Cryptococcus neoformans�(cryptococcal meningitis) Presenting Signs and Symptoms Presentation usually nonspecific at onset. This may be true for > 1 month. Protracted headache and fever may be the only signs Nausea, vomiting, and stiff neck may be absent and focal neurological signs uncommon. Extraneural symptoms: - skin lesions, pneumonitis, pleural effusions and retinitis Fever, malaise, nuchal pain signify a worse prognosis, and nausea and vomiting and altered mental status in terminal stages

21. CSF Values Normal 20% Protein 30-150/dl WBC: 0-100 (monos) Glucose decreased: 50-70mg/dl Culture positive: 95-100% India ink positive: 60-80% Crypt Ag nearly 100% sensitive and specific Diagnostics

23. Management and Treatment Preferred regimen: 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

24. Management and Treatment, continued Alternate regimen: Amphotericin B 0.7 mg/kg/day IV + flucytosine 100mg/kg/day po x 14 days followed by itraconazole 200mg bid for 8 weeks Fluconazole 400 mg/day po x 8 weeks followed by 200 mg once daily Itraconazole 200 mg po tid x 3days, then 200 mg po bid x 8 weeks after initial treatment with amphotericin Fluconazole 400 mg/day po + flucytosine 100 mg/kg/day po

25. Unique features, Caveats If untreated, it is slowly progressive and ultimately fatal 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 It is better prevented than treated

26. Unique features, Caveats, continued 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. Requires lifelong suppressive treatment unless immune reconstitution occurs

27. Viral Infection: Cytomegalovirus (CMV) Presenting Signs and Symptoms Fever ? delirium, lethargy, disorientation, malaise, headache most common Stiff neck, photophobia, cranial nerve deficits less common No focal neurological deficits Gastrointestinal symptoms: diarrhea, colitis, esophageal ulceration appear in 12-15% of patients Respiratory symptoms, i.e, pneumonitis, present ~1%

28. Retinal exam to check for changes. Consult an ophthalmologist 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 UGI endoscopy when indicated Diagnostics

30. Management and Treatment 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 Extra-ocular; ganciclovir and/or foscarnet

31. Unique features, caveats Evolution occurs in less than 2 weeks Usually when CD4<100 � 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 Characteristically involves the retinal vessels which are always abnormal in areas involved by retinitis. There is minimal or no accompanying uveitis � 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

32. Viral Infection: Progressive mulltifocal leukoencephalopathy (PML) Presenting Signs and Symptoms Afebrile, alert, no headache Progressively impaired speech, vision, motor function Cranial nerve deficit and cortical blindness Cognition affected relatively late

33. CT brain scan may be normal or remarkable for areas of diminished density or demyelination (deterioration of the covering of the nerve) PCR of CSF for detection of JC virus JC virus PCR is positive in about 60% of the cases Differential diagnosis: Toxoplasmosis Primary CNS lymphoma � Definitive diagnosis is by brain biopsy (if available) Diagnostics

34. Management and Treatment There is no treatment for this illness ART can improve symptoms and prolong life

35. Unique features, Caveats An end-stage complication of HIV, caused by the JC virus � 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 � Evolution occurs over weeks to months CD4<100

36. Primary CNS lymphoma Presenting Signs and Symptoms Disease progresses slowly over a few weeks Afebrile Headache Focal and multifocal neuro deficits (confusion, hemiplegia, seizures) Mental status change (60%), personality or behavioral Seizures (15%)

38. CT Scan/MRI Location: pre-ventricular in one or more site Prominent edema, irregular and solid on enhancement. � CSF: Normal;�30-50% Protein�10-150/ml WBC�0-100 (monos) Cytology positive in <5% Suspect with negative toxo IgG or failure to respond to empiric toxo treatment Diagnostics

39. Management and Treatment There is no cytotoxic chemotherapy for this disease. Irradiation can help some patients, but is considered palliative� Corticosteroids can also help some patients

40. Unique features, Caveats Primary CNS Lymphoma is RARE in the general community, but affects about 2% of AIDS patients Survival after diagnosis is usually limited (a few months only) Typical end-stage complication of HIV disease Evolution: 2-8 weeks Usually occurs when CD4<100

41. HIV-associated dementia (HAD) Presenting Signs and Symptoms In up to 10% of patients it is the first manifestation of HIV disease Afebrile; general lethargy Triad of cognitive, motor and behavioral dysfunction Early - concentration and memory deficits, inattention, motor-uncoordination, ataxia, depression, emotional lability Late - global dementia, paraplegia, mutism

42. Neuropsychological tests show subcortical dementia Mini-mental exams not very sensitive Diagnostics

44. Management and Treatment Possible benefit from ARV agents that penetrate the CNS (AZT, d4T, ABC, nevirapine) Benefit of AZT at higher dose for mild or moderately severe cases is established; monitor therapy with neurocognitive tests Anecdotal experience indicates response to ART if started early

45. Management and Treatment, continued Sedation for those who are agitated and aggressive�use smaller doses initially to avoid over-sedation Close monitoring: to prevent self-harm, ensure adequate nutrition, diagnose and treat OIs early Psychological support for caregivers�exhausting work; caregivers need regular breaks and may need counseling

46. Painful Sensory and Motor Peripheral Neuropathies  Presenting signs and symptoms Burning pain and numbness in toes and feet, ankles, calves, fingers in more advanced cases Paraplegia Autonomic dysfunction Poor bowel/bladder control Dizziness secondary to postural hypotension Contact hypersensitivity in some cases Mild/moderate muscle tenderness Muscle weakness Later: Reduced pinprick/vibratory sensation; reduced or absent ankle/knee jerks Sweating

47. Electromyography/nerve conduction velocities show predominantly axonal neuropathy CPK usually elevated CSF - look for cytomegalovirus or herpes simplex virus infections�lymphomatous infiltration Spinal fluid to determine etiology Serum B12 and TSH Quantitative sensory testing or thermal thresholds may be helpful Diagnostics

48. Management and Treatment Exclude neurotoxic drugs, alcoholism, diabetes, B12 deficiency, thyroid problems and treat underlying causes if known. Discontinue presumed neurotoxic medication Provide proper nutrition and vitamin supplements

49. Management and Treatment, continnued Pain control: Ibuprofen 600-800 mg po tid or codeine for modest symptoms Amitryptiline 25-50 mg at night Phenytoin 50-100 mg bid or carbamazapine 100-200 mg tid� especially for episodic shooting pain. May have to combine antidepressants with anti-convulsants Methadone or morphine for severe symptoms Lidocaine 10-30% ointment for topical use Physical therapy may be helpful, but may be hampered by pain Nutrition counseling and psychological support

50. Unique features, Caveats Differential: toxoplasmosis, primary CNS lymphoma� Management and treatment is difficult. Consider physical therapy combined with pain management.

51. Neurosyphilis Presenting Signs and Symptoms Can be asymptomatic Headache, fever, photophobia, meningismus ? seizures, focal findings, cranial nerve palsies Tabes dorsalis�sharp pains, parasthesias, decreased DTRs, loss of pupil response General paresis� memory loss, dementia, personality changes, loss of pupil response Meningovascular strokes, myelitis Ocular syphilis�iritis, uveitis, optic neuritis

52. CT Scan/MRI: Aseptic meningitis�may show meningeal enhancement. General paresis�cortical atrophy, sometimes with infarcts. Meningovascular syphilis�deep strokes. May present like dementia. CSF: Protein�45-200/ml WBCs�5-100 (monos) VDRL positive�sensitivity 65%; specificity 100% positive Serum VDRL and FTA-ABS are clue in >90%; false neg serum VDRL in 5-10% with tabes dorsalis or general paresis Definitive diagnosis: positive CSF, VDRL (found in 60-70%) Diagnostics

53. Management and Treatment Give Aq penicillin G, 18-24 mil units/day x 10-14 days Follow-up VDRL every 6 months until negative �Indications to re-treat: CSF WBC fails to decrease at 6 months or CSF still abnormal at 2 years Persisting signs and symptoms of inflammatory response at 3 months Four-fold increase in CSF VDRL at 6 months Failure of CSF VDRL of 1:16 to decrease by two-fold by 2 months or four-fold by 12 months

54. Unique features, Caveats RARE: affects only 0.5% of all HIV/AIDS patients Most common forms in HIV-infected persons are ocular, meningeal, and meningovascular 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. �

55. Unique features, Caveats, continued 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. CD4<350