Björn A. Meyerson

Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder

Chronic electrical stimulation instead of bilateral capsulotomy was done in four selected patients with long-standing treatment-resistant obsessive-compulsive disorder. In three of them beneficial effects were observed.

LONG‐TERM ELECTRICAL CAPSULAR STIMULATION IN PATIENTS WITH OBSESSIVE‐COMPULSIVE DISORDER

OBJECTIVEBecause of the irreversibility of lesioning procedures and their possible side effects, we studied the efficacy of replacing bilateral anterior capsulotomy with chronic electrical capsular stimulation in patients with severe, long-standing, treatment-resistant obsessive-compulsive disorder. METHODSWe stereotactically implanted quadripolar electrodes in both anterior limbs of the internal capsules into six patients with severe obsessive-compulsive disorder. Psychiatrists and psychologists performed a double-blind clinical assessment. A blinded random crossover design was used to assess four of those patients, who underwent continuous stimulation thereafter. RESULTSThe psychiatrist-rated Yale-Brown Obsessive Compulsive Scale score was lower in the stimulation-on condition (mean, 19.8 ± 8.0) than in the postoperative stimulator-off condition (mean, 32.3 ± 3.9), and this stimulation-induced effect was maintained for at least 21 months after surgery. The Clinical Global Severity score decreased from 5 (severe; standard deviation, 0) in the stimulation-off condition to 3.3 (moderate to moderate-severe; standard deviation, 0.96) in the stimulation-on condition. The Clinical Global Improvement scores were unchanged in one patient and much improved in the other three during stimulation. During the stimulation-off period, symptom severity approached baseline levels in the four patients. Bilateral stimulation led to increased signal on functional magnetic resonance imaging studies, especially in the pons. Digital subtraction analysis of preoperative [18F]2-fluoro-2-deoxy-d-glucose positron emission tomographic scans and positron emission tomographic scans obtained after 3 months of stimulation showed decreased frontal metabolism during stimulation. CONCLUSIONThese observations indicate that capsular stimulation reduces core symptoms 21 months after surgery in patients with severe, long-standing, treatment-refractory obsessive-compulsive disorder. The stimulation elicited changes in regional brain activity as measured by functional magnetic resonance imaging and positron emission tomography.

Intracerebroventricular Infusion of Nerve Growth Factor in Three Patients with Alzheimer’s Disease

Nerve growth factor (NGF) is important for the survival and maintenance of central cholinergic neurons, a signalling system impaired in Alzheimer’s disease. We have treated 3 patients with Alzheimer’s disease with a total of 6.6 mg NGF administered continuously into the lateral cerebral ventricle for 3 months in the first 2 patients and a total of 0.55 mg for 3 shorter periods in the third patient. The patients were extensively evaluated with clinical, neuropsychological, neurophysiological and neuroradiological techniques. Three months after the NGF treatment ended, a significant increase in nicotine binding was found in several brain areas in the first 2 patients and in the hippocampus in the third patient as studied by positron emission tomography. A clear cognitive amelioration could not be demonstrated, although a few neuropsychology tests showed slight improvements. The amount of slow-wave cortical activity as studied by electroencephalography was reduced in the first 2 patients. Two negative side effects occurred with NGF treatment: first, a dull, constant back pain was observed in all 3 patients, which in 1 patient was aggravated by axial loading resulting in sharp, shooting pain of short duration. When stopping the NGF infusion, the pain disappeared within a couple of days. Reducing the dose of NGF lessened the pain. Secondly, a marked weight reduction during the infusion with a clear weight gain after ending the infusion was seen in the first 2 patients. We conclude from this limited trial that, while long-term intracerebroventricular NGF administration may cause certain potentially beneficial effects, the intraventricular route of administration is also associated with negative side effects that appear to outweigh the positive effects of the present protocol. Alternative routes of administration, and/or lower doses of NGF, perhaps combined with low doses of other neurotrophic factors, may shift this balance in favor of positive effects.

Nerve growth factor affects11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (Case Report)

SummaryBased on animal research suggesting that nerve growth factor (NGF) can stimulate central cholinergic neurons, the known losses of cholinergic innervation of the cortices in Alzheimers disease (AD), and our experience of infusing NGF to support adrenal grafts in parkinsonian patients, we have initiated clinical trials of NGF infusions into the brain of patients with AD. Here we report a follow-up of our first case, a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF during three months resulted in a marked transient increase in uptake and binding of11C-nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects could be ascribed to the NGF infusion. Taken together, the results of this case study indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.

Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism.

&NA; Neuropathic pain may be effectively relieved by electric stimulation of the spinal cord (SCS). However, the underlying mechanisms for the ensuing pain relief are poorly understood. In a rat model of neuropathy displaying hypersensitivity to innocuous tactile stimuli, (allodynia), we have earlier demonstrated that SCS may normalise withdrawal response thresholds. In the present study, using microdialysis, it is shown that SCS induces a decreased release of the dorsal horn excitatory amino acids (EAA), glutamate and aspartate, concomitant with an increase of the GABA release. Local perfusion with a GABAB‐receptor antagonist in the dorsal horn transiently abolishes the SCS‐induced suppression of the EAA release. Thus, the effect of SCS on neuropathic pain and allodynia may be due to an activation of local GABAergic mechanisms inhibiting the EAA release which is chronically elevated in such conditions.

Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy

&NA; Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity (‘allodynia’) was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The inflammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED‐1), natural killer cells, T lymphocytes, and the pro‐inflammatory cytokines tumor necrosis factor‐&agr; (TNF‐&agr;) and interleukin‐6 (IL‐6), were significantly upregulated in all nerve injured rats in comparison to sham‐operated controls. Interestingly, ED‐1‐, TNF‐&agr;‐ and IL‐6‐positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non‐allodynic ones. The magnitude of the inflammatory response does not seem to relate to the extent of damage to the nerve fibers because axotomized rats displayed much lower upregulation. Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL‐6 and TNF‐&agr;. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED‐1 and IL‐6‐positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro‐inflammatory interleukins after nerve damage could influence the development of neuropathic pain.

Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats.

OBJECTIVE The aim of the present study is to monitor the extracellular gamma-aminobutyric acid (GABA) levels in the lumbar dorsal horn of allodynic rats, which respond to spinal cord stimulation (SCS) with a normalization of the tactile withdrawal threshold. In addition, we monitored the GABA levels in nonresponding and sham-stimulated rats. METHODS Partial constriction injury of the sciatic nerve was performed, and a permanent electrode for SCS was inserted into the spinal canal. The response to SCS was assessed with von Frey hairs in awake animals. Later, microdialysis was performed in the dorsal horn of the spinal cord under halothane anesthesia. The concentration of GABA in the microdialysate was assessed by high-performance liquid chromatography. RESULTS Extracellular GABA levels in rats with sciatic nerve lesions and allodynia (2.3 +/- 0.5 nmol/L) were significantly lower (P < 0.001) than in control rats with intact sciatic nerves (8.1 +/- 1.0 nmol/L), whereas only slightly decreased GABA levels (5.7 +/- 1.1 nmol/L) were detected in nonallodynic rats with sciatic nerve lesions. In the allodynic rats, which respond to SCS by a normalization of the tactile withdrawal threshold, significantly (P < 0.001) increased GABA levels (6.7 +/- 2.3 nmol/L) were detected after SCS. In contrast, neither the allodynic rats, which did not respond to SCS, nor the sham-stimulated allodynic rats displayed increased GABA levels in response to stimulation. CONCLUSION Our results indicate that the development of allodynia, a common symptom in neuropathic pain states, may be linked to a decreased spinal release of GABA. We suggest that an SCS-induced release of GABA could be important for the suppression of allodynia observed in rats after SCS. Similar mechanisms could also be involved in the SCS-induced alleviation of pain in patients with peripheral neuropathy.

A New Classification for Facial Pain

PURPOSEA patient-oriented classification scheme for facial pains commonly encountered in neurosurgical practice is proposed. CONCEPTThis classification is driven principally by the patient’s history. RATIONALEThe scheme incorporates descriptions for so-called “atypical” trigeminal neuralgias and facial pains but minimizes the pejorative, accepting that the physiology of neuropathic pains could reasonably encompass a variety of pain sensations, both episodic and constant. Seven diagnostic labels result: trigeminal neuralgia Types 1 and 2 refer to patients with the spontaneous onset of facial pain and either predominant episodic or constant pain, respectively. Trigeminal neuropathic pain results from unintentional injury to the trigeminal nerve from trauma or surgery, whereas trigeminal deafferentation pain results from injury to the nerve by peripheral nerve ablation, gangliolysis, or rhizotomy in an intentional attempt to treat either trigeminal neuralgia or other facial pain. Postherpetic neuralgia follows a cutaneous herpes zoster outbreak (shingles) in the trigeminal distribution, and symptomatic trigeminal neuralgia results from multiple sclerosis. The final category, atypical facial pain, is synonymous with facial pain secondary to a somatoform pain disorder. Atypical facial pain can be suspected but not diagnosed by history and can be diagnosed only with detailed and objective psychological testing. CONCLUSIONThis diagnostic classification would allow more rigorous and objective natural history and outcome studies of facial pain in the future.

Prolonged relief of neuralgia after regional anesthetic blocks. A call for further experimental and systematic clinical studies.

&NA; Thirty‐eight consecutive patients with neuralgia after peripheral nerve injury were treated with one or two series of peripheral local anesthetic blocks. All patients experienced an initial total relief of ongoing pain for 4–12 h. Evoked pain (hyperalgesia or allodynia), which occurred in 17 patients, was blocked simultaneously with the spontaneous pain. In 18 patients the analgesia outlasted the conduction block and there was a period of complete pain relief of 12–48 h in 13 patients and of 2–6 days in the other 5. In 8 patients there was a second phase of analgesia of 4 h to 6 days duration occurring within 12 h of pain recurrence. Thus, mono‐ or biphasic prolonged complete analgesia occurred in 25 out of 38 patients. A prolonged analgesia may be the result of a central action of the local anesthetic at the spinal level after intra‐axonal incorporation and centripetal axoplasmic transport. To test this hypothesis, an experimental study with [3H]lidocaine was performed in 6 rats. The radioactive local anesthetic was injected into one hind limb foot with the other side serving as a control. Tissue samples from the peripheral nerve, nerve root and the lumbosacral spinal cord segment were analyzed for radioactivity using a scintillation counter technique at various time intervals after the [3H]lidocaine injection. There was a low grade of activity in all samples and no difference between the test side and the control side. Thus these experiments provided no evidence in support of this hypothesis. Various alternative peripheral and central mechanisms are discussed. Further studies specifically directed to these alternatives and with longitudinal controls are prompted.

Effects of spinal cord stimulation on touch-evoked allodynia involve GABAergic mechanisms. An experimental study in the mononeuropathic rat

&NA; There is much evidence that tactile allodynia in rat models of mononeuropathy produced by sciatic nerve constriction is linked to disturbance of spinal GABAergic functions. Spinal cord stimulation (SCS) applied to such animals via chronically implanted electrodes may in some of the animals induce a significant increase of the withdrawal threshold in response to innocuous mechanical stimulation with von Frey filaments applied to the paw of the nerve ligated leg. The present study was performed in mononeuropathic animals with definite signs of tactile allodynia, which did Symbol respond to SCS. GABA and the GABAB‐agonist baclofen were administered intrathecally, in doses per se insufficient to influence the withdrawal thresholds, together with the previously ineffective SCS. This combination resulted in a marked and long‐lasting increase of the thresholds. The GABAA‐agonist muscimol given together with SCS also produced a similar, but less prominent threshold increase. The GABAB‐antagonist 5‐aminovaleric acid (5‐AVA) produced a transient suppression of the threshold increase induced by SCS together with either GABA or baclofen. In contrast, the GABAA‐antagonist bicuculline had no apparent inhibitory effect on the threshold augmentation produced by SCS combined with GABA or baclofen. It is concluded that SCS may operate by upgrading the spinal GABAergic systems and that its potential for producing pain relief is dependent upon the availability of responsive GABA‐containing inhibitory interneurons. Moreover, it seems that the effects of SCS are more linked to the GABAB‐ than to the GABAA‐receptor system. Symbol. No caption available.