Dear Editor,

This very interesting report may well be correct in suggesting an association between mood disorders in general (not just depression) and Parkinson's disease (PD). However a more likely consideration, given the observation that the anti-PD medications were mostly begun within the first six months of starting the mood-treatment drugs, is that the parkinsonian syndrome was drug induced. Lithium and the selective serotonin reuptake inhibitors have been associated with parkinsonism (1- 5)and it is likely that some patients receiving lithium were also taking valproic acid, another drug associated with parkinsonism(1). My own experience has been that lithium induced parkinsonism is underrecognized, but I have no data to support that contention.

Unfortunately the data available for analysis from this study will not be able to distinguish drug induced parkinsonism from idiopathic PD but this problem confounds the interpretation provided.

References

1. Nguyen N, Pradel V, Micallef J, et al. Drug-induced parkinson syndromes. Therapie 2004;59:105-112.

2. Holroyd S, Smith D. Disabling parkinsonism due to lithium: a case report. J Geriatr Psychiatry Neurol 1995;8:118-119.

3. Shopsin B, Gershon S. Congwheel rigidity related to lithium maintenance. m J Psychiatry 1975;132:536-538.

4. Lecamwasam D, Synek B, Moyles K, et al. Chronic litium neurotoxicity presenting as Parkinson's disease. Int Clin Psychopharmacol 1994;9:127- 129.

5. Caley C. Extrapyramidal reactions and the selective serotonin-reuptake inhibitors. Ann Pharmacother 1997;31:1481-1489.

Dear Editor,

Estrogen has multiple effects on brain function and the important one is neuroprotection [1]. It is felt that this sex hormone plays an important role in prevention of viral encephalitis. The incidence of disease was frequent in males as compared to females in all the epidemics of Japanese Encephalitis [2]. Similar pattern is seen in West Nile encephalitis [3]. Oophorectomized mice have rarely been used in viral encephalitis research.

Post viral neuro-endocrine picture is also interesting. Post-encephalitic hypothalamic-pituitary insufficiency was noticed long back [4]. Sub clinical dose of tick-borne encephalitis virus increased the level of plasma testosterone in mice [5]. Inoculation of Herpes virus-1 in rats induced fever, marked motor hyperactivity and aggressive behavior, and increased serum ACTH, corticosterone (CS) and brain prostaglandin-E2 production [6]. D variant of encephalomyocarditis virus caused encephalitis in mice younger than 7 weeks and diabetes past this age [7].

The hypoglycaemia in JE-confirmed patients coincided with the gradual rise in circulating glucagon level, with no significant alterations in insulin, growth hormone and cortisol levels [8]. Progressively diminished insulin responses and significantly lower glucagon levels were seen after 5 months of Venezuelan equine encephalitis virus infection [9].

The efforts to treat the encephalitis cases with hormones have also been attempted. A 24-month-old child treated with ACTH developed fulminant “Subacute sclerosing panencephalitis” 17 months after measles infection [10]. Postvaricella encephalitis in 9-year-old boy was treated successfully with corticotropin [11]. Emotional incontinence and amnesia resulting from mumps encephalitis in 7-year-old girl was treated successfully with thyrotropin-releasing hormone [12]. Experimental parkinsonism in rats induced by Japanese encephalitis virus is improved using thyrotropin-releasing hormone [13].

It appears that case definition of any viral encephalitis should have endocrinilogical dimension particularly estrogen.

References

1.Cutter WJ, Norbury R, Murphy DG.Oestrogen, brain function, and neuropsychiatric disorders. J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):837-40.[Full Text]

2.Kaur R, Agarwal CS, Das D. An investigation into the JE epidemic of 2000 in Upper Assam--a perspective study. J Commun Dis. 2002 Jun;34(2):135-45. [Medline]

Kalita J, Misra UK. Brainstem auditory evoked potential in Japanese encephalitis. J Neurol Sci. 1999 May 1;165(1):24-7.[Medline]

Prasad SR, Kumar V, Marwaha RK, Batra KL, Rath RK, Pal SR. An epidemic of encephalitis in Haryana: serological evidence of Japanese encephalitis in a few patients. Indian Pediatr. 1993 Jul;30(7):905-10. [Medline]

Vajpayee A, Mukherjee MK, Chakraborty AK, Chakraborty MS. Investigation of an outbreak of Japanese encephalitis in Rourkela City (Orissa) during 1989. J Commun Dis. 1991 Mar;23(1):18-21. [Medline]

Poneprasert B.Japanese encephalitis in children in northern Thailand. Southeast Asian J Trop Med Public Health. 1989 Dec;20(4):599-603. [Medline]

Kamala CS, Rao MV, George S, Prasanna NY. Japanese encephalitis in children in Bellary Karnataka. Indian Pediatr. 1989 May;26(5):445-52.[Medline]

3.O'Leary DR, Marfin AA, Montgomery SP, Kipp AM, Lehman JA, Biggerstaff BJ, Elko VL, Collins PD, Jones JE, Campbell GL. The epidemic of West Nile virus in the United States, 2002. Vector Borne Zoonotic Dis. 2004 Spring;4(1):61-70.[Medline]

4.Kupari M, Pelkonen R, Valtonen V. Post-encephalitic hypothalamic-pituitary insufficiency. Acta Endocrinol (Copenh). 1980 Aug;94(4):433-8.[Medline]

5.Moshkin M, Gerlinskaya L, Morozova O, Bakhvalova V, Evsikov V. Behaviour, chemosignals and endocrine functions in male mice infected with tick-borne encephalitis virus. Psychoneuroendocrinology. 2002 Jul;27(5):603-8.[Medline]

6.Ben-Hur T, Itzik A, Barak O, Asher Y, Becker Y, Yirmiya R, Weidenfeld J. Immunization with a nonpathogenic HSV-1 strain prevents clinical and neuroendocrine changes of experimental HSV-1 encephalitis. J Neuroimmunol. 2004 Jul;152(1-2):5-10.[Medline]

7.Giron DJ, Cohen SJ, Lyons SP, Trombley ML, Gould CL. Virus-induced diabetes mellitus in ICR Swiss mice is age dependent. Infect Immun. 1983 Aug;41(2):834-6.[Full Text]

8.Tandon A, Singh A, Atrishi E, Saxena SK, Mathur A. Alteration in plasma glucose levels in Japanese encephalitis patients. Int J Exp Pathol. 2002 Feb;83(1):39-46.[Medline]

Khanna N, Mathur A, Bharadwaj M, Chaturvedi UC. Induction of hypoglycaemia in Japanese encephalitis virus infection: the role of T lymphocytes. Clin Exp Immunol. 1997 Feb;107(2):282-7.[Medline]

9.Bowen GS, Rayfield EJ, Monath TP, Kemp GE.Studies of glucose metabolism in rhesus monkeys after Venezuelan equine encephalitis virus infection. J Med Virol. 1980;6(3):227-34.[Medline]

10.Serdaroglu G, Kutlu A, Tekgul H, Tutuncuoglu S. Subacute sclerosing panencephalitis: a case with fulminant course after ACTH. Pediatr Neurol. 2004 Jul;31(1):67-70.[Medline]

11.Bauman ML, Bergman I. Postvaricella encephalitis. Arch Neurol. 1984 May;41(5):556-8.[Medline]

12.Kubo T, Kobayashi O, Nozaki M, Kurokawa T, Tamura K, Nonoyama S. Successful thyrotropin-releasing hormone therapy for emotional incontinence and amnesia resulting from mumps encephalitis. Pediatr Infect Dis J. 2004 Dec;23(12):1175-6.[Medline]

13.Ogata A, Nagashima K, Yasui K, Matsuura T, Tashiro K. Sustained release dosage of thyrotropin-releasing hormone improves experimental Japanese encephalitis virus-induced parkinsonism in rats. J Neurol Sci. 1998 Aug 14;159(2):135-9.[Medline]

Dear Editor

In response to whether an HIV-associated vasculopathy may be reversible [1], we describe a man with severe cognitive impairment due to an isolated HIV-associated cerebral vasculopathy, likely to be a vasculitis. With initiation of highly active anti-retroviral treatment (HAART), and without additional antimicrobial or immunosuppressive treatment, he made a major recovery over six weeks to independent living in the community.

A 49 year-old man from Zimbabwe living in the UK for 5 years presented after an unwitnessed collapse and two weeks of cognitive decline. He had received a course of oral corticosteroids for parotitis two months earlier. He had no other medical history and no conventional vascular risk factors. On examination he was encephalopathic with severe global cognitive impairment confirmed on formal psychometry. He knew his name, but all other responses on MMSQ were incorrect. Speech was very slow and he could follow some one-step commands. There was right hemineglect and he could not stand unsupported. There were no additional neurological signs in the limbs allowing for the neglect, including normal power. He was meningitic, but not distressed, and afebrile. No ictal activity was observed. There was residual right parotid swelling. Ocular, cardiac, respiratory, abdominal, skin and joint examinations were normal.

HIV antibody was positive, with a viral load of 500 000 copies/mL and the CD4 count was 94 cells/mm3. The ESR was 120mm/hour. Serum amylase was mildly elevated at 215 U/L, a parotid origin of this could not be confirmed. A homogenous-staining antinuclear antibody was weakly positive at 1:100, increasing after one week to >1:1000. A weakly staining ANCA was positive, but testing for MPO and PR3 antigens were negative, along with other autoimmune markers. Serial blood cultures were negative. CSF showed 18 nucleated cells, mainly lymphocytes with some macrophages consistent with a reactive pleocytosis, and CSF protein elevated at 0.72g/L. Chest radiography and abdominal ultrasonography were normal. Transthoracic and transoesophageal echocardiography showed normal cardiac valves.

MRI brain with gadolinium enhancement demonstrated numerous lesions in both cerebral hemispheres with a preponderance of the left hemisphere (Figure 1A-D). The large left occipital lesion had acutely restricted diffusion on DWI and ADC images (not shown). The clinical impression was of a cerebral vasculitis in the context of HIV infection. Brain biopsy was performed of the superficial left occipital lesion to exclude additional pathology such as concomitant fungal infection. The biopsy showed only non-specific necrosis, with no specific features of a vasculitis. There was also no evidence of emboli, lymphoma, fungi, viral inclusions or mycobacteria identified. Cerebral angiography (Figure 1E) confirmed a macro and microangiopathic vasculopathy. PCR of both CSF and biopsied brain tissue was negative for VZV, HSV, JC virus, EBV, CMV, HHV6, adenoviridae and enteroviridae. Testing of blood and CSF was also negative for Aspergillus, Cryptococcus, Toxoplasma, Treponema, Borrelia, Mycobacteria and current hepatitis A, B or C.

Empiric intravenous aciclovir was started on presentation but discontinued when viral PCR testing returned negative and there had been no clinical improvement. HAART was initiated (Fosamprenavir, Ritonavir, Kivexa) with Cotrimoxazole for pneumocystis prophylaxis. He made a slow clinical improvement, walking at 3 weeks and oriented at 6 weeks, and was able to be discharged home. He has subsequently returned to work. MRI at two months showed maturation of the larger lesions, with no new abnormalities. We did not find earlier reports of major clinical improvement in HIV-associated cerebral vasculopathy or vasculitis with HAART alone, without the use of immunosuppressive treatment.

The distribution of the cerebral lesions on MRI, the macro and microangiopathy on cerebral angiography, the CSF pleocytosis and the reversible encephalopathy together suggest that the vasculopathy here is most likely due to a cerebral vasculitis. The brain biopsy contained necrotic material consistent with an infarct, therefore did not prove a vasculitis. The elevated ANA was in isolation, with no other clinical or serological features of a primary rheumatological disorder. HIV was the only cause identified, and there was a clinical response to treatment for this.

HIV-associated intracranial vasculopathy is recognised in association with young-onset stroke, found in 6 of 67 young-onset stroke patients in the recent series [2]. Biopsy-proven HIV-associated cerebral vasculitis has been identified after initiation of HAART, and is thought in these cases, at least in part, to be part of an immune reconstitution inflammatory syndrome (IRIS)[3, 4]. This often requires temporarily stopping the antiretroviral treatment and additional immunosupression. In the case we describe, the neurological presentation was prior to the diagnosis of HIV and the initiation of antiretroviral treatment.

It can be tempting in such cases to use immunosuppressive treatments, as in a primary CNS vasculitis, but this has theoretical risks of exposing the already immunocompromised patient to additional risk. We propose that thorough investigation for other causes, along with careful clinical observation after initiation of HAART was the appropriate management in this case with an excellent recovery.

Figure Legend: Figure 1. A,B. FLAIR MRI axial images showing multiple hyperintensities with preponderance for the left cerebral hemisphere. CD. T1 Gadolinium-enhanced axial MRI images showing additional enhancing lesions not seen on the T2 and FLAIR sequences. E. Digital subtraction angiography after left internal carotid artery injection. There is delayed filling of the left middle cerebral artery (MCA) territory, shown in the early arterial phase having mostly filled via leptomeningeal collaterals from the left anterior cerebral artery (ACA). The ACA territory is entering the venous phase, having completed arterial filling earlier in the sequence. This suggests stenosis of proximal MCA segments. In addition, there is evidence of microangiopathy with segmental stenosis of MCA arterioles indicated by the arrows.

Word Count Main text: 799 Figure legend: 116

References

1. Connor, M., Stroke in patients with human immunodeficiency virus infection. J Neurol Neurosurg Psychiatry, 2007. 78(12): p. 1291.

2. Tipping, B., et al., Stroke in patients with human immunodeficiency virus infection. J Neurol Neurosurg Psychiatry, 2007. 78(12): p. 1320-4.

3. van der Ven, A.J., et al., Cerebral vasculitis after initiation antiretroviral therapy. Aids, 2002. 16(17): p. 2362-4.

4. Bonkowsky, J.L., et al., Cerebral aneurysms in a child with acquired immune deficiency syndrome during rapid immune reconstitution. J Child Neurol, 2002. 17(6): p. 457-60.

Dear Editor

We read with interest the letter by Dr Gupta on our paper entitled “A diffusion tensor magnetic resonance imaging study of brain tissue from patients with migraine”.[1] Nevertheless, we believe that he missed the main result of this study as well as the scope for which it was designed and conducted. The aim of this study was to investigate whether occult’ tissue damage, which goes undetected when using conventional MRI, could be detected in patients with migraine, as it is the case in many other neurological conditions.[2] The main result was that such changes do indeed occur in the normal-appearing brain tissue (NABT) of these patients (and, to the best of our knowledge, this is the first time that such a finding has been shown). Clearly, this sets up the stage for future research, which might put these observations in a clinical perspective, but this was not (and could not be) the aim of a preliminary study which has first to show that these NABT abnormalities do exist in patients with migraine.

Against this background, we can now consider the specific points raised by Dr Gupta.
1. NABT changes and laterality of headache. We understand the enthusiasm of Dr. Gupta for his own work, but we have difficulties in understanding how “more definitive clinico-pathological correlation” can be achieved by considering “the lateralization of the observed white matter abnormalities to the aura as well as to the headache”. We believe this approach might strengthen clinical/MRI correlations, but we cannot see how it can provide pathologically specific information about the nature of the NABT changes we described. Dr. Gupta’s reference to the lateralization of aura is also puzzling, considering his following comment.

2. Patients with aura vs. patients without aura. We are aware that these two patients’ groups share "more similarities than differences". This was one of the reasons why we run such an additional comparison, which, anyway, constituted only a marginal point of this study (about one line in the Results). Dr Gupta should welcome these results with enthusiasm, since they represent additional scientific evidence to the point he made.

3. NABT changes and pathogenesis. Again, it is unclear how pharmacological studies might help in understanding the nature of NABT changes. We do not know whether such NABT changes do or do not have a "pathogenetic implication" – this study was not designed to respond to this question and further studies are warrented to clarify this issue. Dr Gupta’s statement that "radiological changes in the brain [...] are, therefore, probably secondary features that [...] do not have any pathogenetic implication” is likely to be an example of an enthusiastic, but scientifically unproven, speculation.

References

(1) Rocca MA, Colombo B, Inglese M, Codella M, Comi G, Filippi M. A diffusion tensor magnetic resonance imaging study of brain tissue from patients with migraine. J Neurol Neurosurg Psychiatry 2003; 74: 501-503.

(2) Filippi M. In-vivo tissue characterization of multiple sclerosis and other white matter diseases using magnetic resonance based techniques. J Neurol 2001; 248: 1019-1029. Review.