Table 2.

Studies that have examined the efficacy of drugs in patients with cognitive deficits stemming from primary infection of the central nervous system: summary of study.

Authors (year), country/cohort/ infectious agent	Sample size/age (mean ± SD) yr/sex (%M)/duration of illness (DI, yr)/attrition (by group)	Intervention type, drug, duration (by groups)	Outcome/assessment	Findings/adverse effects
Prasad et al (2013),[36] USA/Western Psychiatric Inst. & Clinic, Pittsburgh, & Wayne State University, Detroit/ HSV-1	G1 (n = 12) Age: 29.54 ± 9.44 Sex: 50% M DI: 3.49 ± 2.82 Attrition = 25% G2 (n = 12) Age: 28.67 ± 8.47 Sex: 58% M DI: 5.59 ± 3.08 Attrition = 33%	Double-blind PLA-RCT G1: VAV + AP G2: PLA + AP/ 18 wks	Working memory (total & 2-back), Immediate verbal memory (processing speed & accuracy)/ PennCNB	G1 vs G2: ↑ in working + verbal memory & visual obj learning/ G1: constipation, stomach pain, motion sickness, occasional muscle twitch, tremor, and upset stomach G2: leg cramps Reported within both groups: drooling, muscle tightness, mild tremors, akathisia, bloating of the stomach, feeling tired, elbow pain, increased sexual drive, insomnia
Berende et al (2019),[23] Netherlands/Sint Maartenskliniek & Radboud University Medical Center/LD	G1 (n = 86) Age: 48.3 ± 12.6 Sex: 54% M DI: 2.7* Attrition = 23% G2 (n = 96) Age: 47.5 ± 13.0 Sex: 57% M DI: 2.8* Attrition = 25% G3 (n = 98) Age: 50.3 ± 9.9 Sex: 52% M DI = 2.3* Attrition = 26%	PLA-RCT G1: CTX + DOX (NR) G2: CTX + CLR-HCQ (NR) G3: CTX + PLA 14 wks	Episodic memory, Attention/working memory, Verbal fluency, Speed Of info processing, Executive function/ RAVLT, DST, TMT-A, SCWT, DSST & CFT	↑ cog performances at wk 14, 26, & 40 compared to BL: not specific to a TX group. LT AB TX ≠ better cog performance than ST AB TX/NR
Breier et al (2018),[25] USA/Indiana University School of Medicine/HSV-1	G1 (n = 40) Age: 30.0 ± 6.2 Sex: 65% M DI: 4.4 ± 2.3 Attrition = 32.5% G2 (n = 34) Age: 29.9 ± 6.1 Sex: 58.8% M DI: 4.2 ± 2.7 Attrition = 26.5% G3 (n = 46) Age: 25.4 ± 4.9 Sex: 89.1% M DI: 3.6 ± 2.1 Attrition = 30.4% G4 (n = 50) Age: 27.4 ± 6.0 Sex: 76% M DI: 3.3 ± 1.90 Attrition = 24%	Double-blind PLA-RCT G1: HSV+ & PLA G2: HSV+ & VAV G3: HSV- & PLA G4: HSV- & VAV 16 wks	Working memory, Visuospatial memory, Letter-number sequencing, Spatial span/ MATRICS & MCCB	VAV failed to demonstrate SGNFT treatment effects on the 2 primary cog outcome measures: the MCCB working memory composite & visuospatial memory scores. VAV add-on therapy may be beneficial for cog impairments but not psychotic SX/ NR but 18.8% discontinued due to “adverse event”
Fallon et al (1999),[17] USA/ NR/ LD	G1 (n = 5) Attrition = CD G2 (n = 7) Attrition = CD G3 (n = 7) Attrition = CD G4 (n = 4) Attrition = CD Age: 42.7 ± 13.25 Sex: 30% M DI: 1.78 ± 1.85	Uncontrolled Study G1: No Treatment G2: Oral AB (NR) G3: IV-AB (NR) G4: IM-AB (NR) 16 wks	Verbal memory, Visual memory Attention, Delayed memory, General memory, Verbal fluency/ WAIS, WMS, & COWAT	T2: G1 overall & individual cog score ↑ than G2; G3 greatest ↑ in cog; No SGNFT correlation b/w DOT on AB & ↑ composite z-score; Repeated AB treatment may ↑ cog in pts/ NR
Fallon et al (2008),[29] USA/New York State Psychiatric Institute and Columbia University Medical Center/LD	G1 (n = 23) Age: 45.3 ± 13.7 Sex: 39% M Attrition = 13% G2 (n = 14) Age: 44.8 ± 12.7 Sex: 42.9% M Attrition = 14% DI: 9.0 ± 6.8	PLA-RCT G1: IV CTX G2: IV PLA 10 wks	Motor, Psychomotor, Attention, Verbal memory, Visual memory, Working memory, Fluency/ WMS- III, N-Back Test, BVRT, BSRT, LRT, CPT, Stroop task, COWAT, CFT, finger tapping, SRT, CRT, TMT-A, TMT-B & digital symbol	12 wk: G1 ↑ in all cog domains; 24 wk: G1 & G2 ↑ in cog; IV CTX = ST ↑ in cog for LD pts/ G1: thrombus, hemolytic anemia, 3 additional Pts discontinued due to “adverse event” G2: Systemic infection, intolerable joint pain
Bhatia et al (2018),[24] India/ Dr Ram Manohar Lohia Hospital, Delhi/ HSV-1	G1 (n = 30) Age: 31.77 ± 8.55 Sex: 50% M DI: 4.87 ± 2.01 Attrition = 17% G2 (n = 32) Age: 30.75 ± 8.68 Sex: 56% M DI: 4.96 ± 2.35 Attrition = 3.1%	PLA-RCT G1: AP + VAV G2: AP + PLA 16 wks	Abstraction & mental flexibility, Attention, Face memory, Spatial memory, Working memory, Spatial ability, Sensorimotor, Emotion/ PennCNB & EMOD	BL: No SGNFT differences b/w G1 & G2 cog functions except spatial ability; Group 1 ↑ in EMOD but not other cog functions/ G1: thrombus, hemolytic anemia, 3 additional Pts discontinued due to “adverse event” G2: Systemic infection, intolerable joint pain
Kaplan et al (2003),[31] USA/ NR/ LD	G1 (n = 39) Attrition = 23% G2 (n = 39) Attrition = 31% G3 (n = 25) Attrition = 20% G4 (n = 26) Attrition = 19% Age: >18 Sex: 51% M DI: 4.01 ± 2.89	Double-blind PLA-RCT G1: LD(+) & AB (2g/d) G2: LD(+) & PLA G3: LD(−) & AB G4: LD(−) & PLA 13 wks	Attention & Speed of info processing, Learning & memory, Word fluency/RAVLT, BVRT, SDMT, & CalCAP	↑ cog functioning not specific to group, treatment, or interaction effects; Sero(+) & sero(−) Pts ↑ cog functioning; Additional AB = no ↑ cog function/ NR
Krupp et al (2003),[32] USA/ Suffolk County, Long Island/ LD	G1 (n = 28) Age: 48.0 ± 11.8 Sex: 46.4% M DI: NR Attrition = 29% G2 (n = 24) Age: 47.0 ± 9.7 Sex: 48.2% M DI: NR Attrition = 29%	Double-blind PLA-RCT G1: AB G2: PLA 4 wk	Cog processing (mental) speed/ AAT	6 mo FU: no SGNFT ↑ cog function or group differences; AB treatment ≠ ↑ cog performance in pts w/ LD/ G1: Diarrhea, anaphylaxis, minor allergic reaction G2: IV sepsis
Otto et al (2004),[34] Germany/German National CJD Surveillance Unit, Goettingen/CJD	G1 (n = 13) Age: 57.0 ± 9.6 Sex: 61.5% M DOI: NR Attrition = 7.7% G2 (n = 15) Age: 61.0 ± 10.3 Sex: 50.0% M DOI: NR Attrition = 13%	Double-blind PLA-RCT G1: FLU G2: PLA 5.5 wk	Long-term & short-term memory, Attention, Executive function, Language, Spatial processing/ADAS, MMSE & GoeCJDDT	G1 had SGNFT in ↓ cog deficits than G2; FLU has SGNFT effects on cog in pts w/ CJD/ G1: muscle weakness G2: lack of tolerability Unspecified group: gastrointestinal bleeding, urticaria

Significant: statistically significant effect was detected (P < .05); Non-significant trend: effect was noted however no statistically significant result was detected.

AAT = alpha-arithmetic test, AB = antibiotics, ADAS = Alzheimer’s Disease Assessment Scale, AP = Antipsychotics, Auditory Verbal learning test, BL = baseline, BSRT = Buschke Selective Reminding Test, BVRT = Benton Visual Retention Test, CalCAP = California Computerized Assessment Package, CFT = Category Fluency Test, CLR-HCQ = clarithromycin-hydroxychloroquine, cog = cognitive/cognition, COWAT = Controlled Oral Word Association Test, CPT = Continuous Performance Test, CRT = Choice Reaction Time, CTX = ceftriaxone, DI = duration of illness, DOT = duration of time, DOX = doxycycline, DSST = Symbol-Digit Substitution Test, DST = Digit Span Test, EMOD = Emotion Identification & Discrimination, F = female(s), FLU = Flupirtine maleate, FU = follow-up, G = group, GoeCJDDT = Goettingen CJD Dementia Test, HSV-1 = herpes simplex virus 1, IM = Intramuscular, Inst. = Institute, ITT = intention to treat, IV = intravenous, LD = lyme disease, LRT = Logical Reasoning Test, LT = long-term, M = male(s), MATRICS = Measurement and Treatment Research to Improve Cognition in Psychosis, MCCB = MATRICS Consensus Cognitive Battery, MMSE = Mini-Mental State Examination, NR = not reported, Obj = object, PennCNB = penn computerized neurocognitive battery, PLA = placebo, Pts = patients, RAVLT = Rey, RCT = randomized controlled trial, SCWT = Stroop Color-Word Test, SDMT = Symbol Digit Modalities Test, SGNFT = significant, SRT = Simple Reaction Time, ST = short-term, SX = symptoms, TMT-A = Trail Making Test Part A, TMT-B = Trail Making Test Part B, TX = Treatment, VAV = Valacyclovir, WAIS = Wechsler Adult Intelligence Scale, WMS = Wechsler Memory Scale.

^*Median stated.